rs139617644

Variant names:

• chr11-68049080-G-A
• rs139617644
• NM_006019.4:c.1674-1G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006019.4(TCIRG1):​c.1674-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,613,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: TCIRG1 NM_006019.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 9.45

Genes affected

TCIRG1 (HGNC:11647): (T cell immune regulator 1, ATPase H+ transporting V0 subunit a3) This gene encodes a subunit of a large protein complex known as a vacuolar H+-ATPase (V-ATPase). The protein complex acts as a pump to move protons across the membrane. This movement of protons helps regulate the pH of cells and their surrounding environment. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, and receptor-mediated endocytosis. V-ATPase is comprised of a cytosolic V1 domain and a transmembrane V0 domain. Alternative splicing results in multiple transcript variants. Mutations in this gene are associated with infantile malignant osteopetrosis. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.4, offset of 1, new splice context is: cctccctcttgcccgccaAGcac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-68049080-G-A is Pathogenic according to our data. Variant chr11-68049080-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68049080-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCIRG1	NM_006019.4	c.1674-1G>A		splice_acceptor_variant, intron_variant	Intron 14 of 19	ENST00000265686.8	NP_006010.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCIRG1	ENST00000265686.8	c.1674-1G>A		splice_acceptor_variant, intron_variant	Intron 14 of 19	1	NM_006019.4	ENSP00000265686.3

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152266 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251008 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135778

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000305 AC: 445 AN: 1461022 Hom.: 0 Cov.: 33 AF XY: 0.000290 AC XY: 211 AN XY: 726890

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.000376

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152384 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74526

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000258 Hom.: 0

Bravo AF: 0.000181

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive osteopetrosis 1 Pathogenic:10

Feb 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1674-1G>A variant is located in a canonical splice-site, and it is predicted to alter gene function due to either exon skipping or nonsense-mediate decay – NMD, and the variant is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 189246; PMID: 10888887; 11532986; 15300850) - PS4. The variant is present at low allele frequencies population databases (rs139617644 – gnomAD 0.001839%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The c.1674-1G>A was detected in trans with a pathogenic variant (PMID: 10888887) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Feb 23, 2023

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.016%). This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000189246 / PMID: 10888887). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 15, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1674-1G>A variant in TCIRG1 has been reported in 3 unrelated patients affected with autosomal recessive infantile malignant osteopetrosis. Two of the patients were compound heterozygotes and one was homozygous (Frattini 2000). The variant has further been identified in 0.02% (2/8588) of European American chromosomes and 0.02% (1/4400) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -

Oct 01, 2021

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_006019.3(TCIRG1):c.1674-1G>A is a canonical splice variant classified as pathogenic in the context of autosomal recessive osteopetrosis type 1. c.1674-1G>A has been observed in cases with relevant disease (PMID: 15300850). Functional assessments of this variant are not available in the literature. c.1674-1G>A has been observed in population frequency databases (gnomAD: NFE 0.03%). In summary, NM_006019.3(TCIRG1):c.1674-1G>A is a variant in a canonical splice site in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. ​Please note: this variant was assessed in the context of healthy population screening. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 21, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 22, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TCIRG1 c.1674-1G>A variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.1674-1G>A variant has been reported in three studies in which it is found in a total of 14 individuals with osteopetrosis including at least three homozygotes and 11 compound heterozygotes (Frattini et al. 2000; Sobacchi et al. 2001; Susani et al. 2004). The c.1674-1G>A variant was absent from 520 control chromosomes and is reported at a frequency of 0.000316 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies using RT-PCR revealed that the c.1674-1G>A variant causes abnormal splicing of the TCIRG1 transcript which was not detected in normal controls (Frattini et al. 2000). Western blot analysis of the cell lysates from two compound heterozygotes did not detect the presence of any TCIRG1 protein (Frattini et al. 2000). Based on the collective evidence and potential impact of splice site variants, the c.1674-1G>A is classified as pathogenic for osteopetrosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Dec 28, 2021

Genomics Facility, Ludwig-Maximilians-Universität München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:6

Mar 17, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 14 of the TCIRG1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs139617644, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with autosomal recessive osteopetrosis (PMID: 10888887, 15300850). This variant is also known as G10106A. ClinVar contains an entry for this variant (Variation ID: 189246). Studies have shown that disruption of this splice site results in abnormally spliced transcripts, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 10888887). For these reasons, this variant has been classified as Pathogenic. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 27, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Western blot analysis did not detect mutant protein, supporting this variant results in a null allele (Frattini et al., 2000); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11532986, 30898715, 25525159, 10888887, 29431110, 10942435, 15300850, 31589614, 31949009, 24753205) -

Oct 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TCIRG1-related disorder Pathogenic:1

Jul 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TCIRG1 c.1674-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant (sometimes referred to as G10106A in the literature) has been reported in the homozygous and compound heterozygous states in several individuals with autosomal recessive osteopetrosis (see for example, Frattini et al. 2000. PubMed ID: 10888887; Capo et al. 2021. PubMed ID: 31949009). In vitro RNA studies confirmed that this variant disrupts splicing which leads to frameshift and no detectable protein (Frattini et al. 2000. PubMed ID: 10888887). This variant is reported in 0.032% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in TCIRG1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Osteopetrosis Pathogenic:1

Jul 23, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TCIRG1 c.1674-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a 5 splicing donor site and another predicts the variant abolishes a 3 acceptor site. Three predict the variant weakens a 3 acceptor site. At least one publication reports experimental evidence that this variant results in aberrant splicing (Frattini_2000). The variant allele was found at a frequency of 0.00016 in 251008 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in TCIRG1 causing Osteopetrosis (0.00016 vs 0.0016), allowing no conclusion about variant significance. c.1674-1G>A has been reported in the literature in multiple individuals (both compound heterozygous and homozygous) affected with Osteopetrosis (e.g. Frattini_2000, Sobacchi_2001, Susani_2004). These data indicate that the variant is very likely to be associated with disease. Western blot analysis of EBV-immortalized cells from two compound heterozygous patients carrying the variant of interest and another variant showed no TCIRG1 protein expression (Frattini_2000). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.49		Position offset: 2
DS_AL_spliceai		0.96		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139617644; hg19: chr11-67816547;