rs139617644

Positions:

chr11-68049080-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_006019.4(TCIRG1):c.1674-1G>A variant causes a splice acceptor 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

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 9.45

Variant links:

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]

TCIRG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
TCIRG1	NM_006019.4 linkuse as main transcript	c.1674-1G>A		splice_acceptor_variant		ENST00000265686.8	NP_006010.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCIRG1	ENST00000265686.8 linkuse as main transcript	c.1674-1G>A		splice_acceptor_variant		1	NM_006019.4	ENSP00000265686	P1	Q13488-1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152266

Hom.:

Cov.:

show subpopulations

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:

AN:

251008

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135778

show subpopulations

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.:

Cov.:

AF XY:

0.000290

AC XY:

211

AN XY:

726890

show subpopulations

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:

AN:

152384

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74526

show subpopulations

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.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive osteopetrosis 1

Pathogenic:10

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 22, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 15, 2015	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 01, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomics Facility, Ludwig-Maximilians-Universität München	Dec 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 05, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	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 disrupted 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 introduces a premature termination codon (PMID: 10888887). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2019	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 17, 2022	- -

TCIRG1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 23, 2020

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

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

D;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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over