11-68041392-A-T

Variant names:

• chr11-68041392-A-T
• rs751881962
• NM_006019.4:c.117+4A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The NM_006019.4(TCIRG1):​c.117+4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,603,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: TCIRG1 NM_006019.4 splice_region, intron
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 1.98
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive osteopetrosis

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet
• autosomal recessive osteopetrosis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• autosomal dominant severe congenital neutropenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive osteopetrosis 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dysosteosclerosis

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-68041392-A-T is Pathogenic according to our data. Variant chr11-68041392-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCIRG1	NM_006019.4	c.117+4A>T		splice_region_variant, intron_variant	Intron 2 of 19	ENST00000265686.8	NP_006010.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCIRG1	ENST00000265686.8	c.117+4A>T		splice_region_variant, intron_variant	Intron 2 of 19	1	NM_006019.4	ENSP00000265686.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152030 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000443 AC: 11 AN: 248134 AF XY: 0.0000520

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000903

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000365 AC: 53 AN: 1451214 Hom.: 0 Cov.: 29 AF XY: 0.0000402 AC XY: 29 AN XY: 721898

African (AFR) AF: 0.00 AC: 0 AN: 33288

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.00 AC: 0 AN: 86082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5660

European-Non Finnish (NFE) AF: 0.00000997 AC: 11 AN: 1103768

Other (OTH) AF: 0.000117 AC: 7 AN: 60022

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152030 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74266

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000522 Hom.: 0

Bravo AF: 0.0000453

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive osteopetrosis 1 Pathogenic:7

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 12, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jan 26, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Nov 15, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.003%). Predicted Consequence/Location: Intron variant: previously reported to result in an inframe deletion located in a critical region of the funtional domain (PMID: 15300850, 10942435, 24989235) In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.67 (spliceogenicity >=0.2, non-spliceogenicity <0.1)]. Intron variant: previously reported to result in an inframe deletion located in a critical region of the funtional domain (PMID: 15300850, 10942435, 24989235) Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Mar 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 19, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive osteopetrosis 1 (MIM#259700). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Patients may present with variable features (PMID: 17400532). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Minigene assay and RT-PCR show this variant results in the activation of an upstream cryptic splice site, causing an in-frame deletion of 14 amino acids in exon 2 and also exon 2 skipping (PMID: 15300850, 10942435, 24989235). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (11 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same position is present in gnomAD (v2) at a frequency of 0.0003269 (10 heterozygotes, 0 homozygotes). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar, and has been observed in one compound heterozygous individual with osteopetrosis, and five unrelated homozygous individuals with osteopetrosis (PMID: 15300850, 10942435, 24989235). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_006019.2(TCIRG1):c.2066G>A; p.(Trp689*)) in a recessive disease. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Mar 15, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 2 of the TCIRG1 gene. It does not directly change the encoded amino acid sequence of the TCIRG1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 14 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs751881962, gnomAD 0.09%). This variant has been observed in individuals with osteopetrosis (PMID: 10942435, 15300850, 19507210, 24989235). This variant is also known as IVS2+4A>T. ClinVar contains an entry for this variant (Variation ID: 5462). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in 2 (PMID: 10942435, 24989235). For these reasons, this variant has been classified as Pathogenic.

Dec 14, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies indicate that this splice site variant results int the activation of an upstream cryptic splice donor site and causes an in-frame deletion of exon 2 (Susani et al., 2004); This variant is associated with the following publications: (PMID: 30537558, 25046648, 15300850, 24989235, 10942435, 25525159)

Inborn genetic diseases Pathogenic:1

Jun 28, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.117+4A>T intronic alteration consists of an A to T substitution 4 nucleotides after exon 2 (coding exon 1) of the TCIRG1 gene. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (11/248134) total alleles studied. The highest observed frequency was 0.09% (9/9972) of Ashkenazi Jewish alleles. This alteration has been reported in the homozygous state in individuals with features of autosomal recessive osteopetrosis and was shown to segregate with disease in families (Anderson, 2015; Kornak, 2000). Haplotype analysis revealed that the carrier frequency in the Ashkenazi Jewish population is due to a single founder mutation (Anderson, 2015). Functional studies using RT-PCR analysis demonstrated that this alteration affected splicing, resulting in a 14 amino acid deletion located in the N-terminal, intracellular portion of the protein (Kornak, 2000). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as pathogenic.

TCIRG1-related disorder Pathogenic:1

May 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TCIRG1 c.117+4A>T variant is predicted to interfere with splicing. This variant in the homozygous or compound heterozygous condition has been found in multiple patients with autosomal recessive osteopetrosis, and a functional study suggested that this variant causes splicing defects (Susani et al. 2004. PubMed ID: 15300850). This variant has been reported to be a founder mutation in the Ashkenazi Jewish population (Anderson et al. 2015. PubMed ID: 24989235). This variant is interpreted as pathogenic.

Autosomal recessive osteopetrosis Pathogenic:1

Dec 28, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.117+4A>T variant in TCIRG1 has been reported in the homozygous state in at least 6 individuals and in the compound heterozygous state with another disease-causing variant in TCIRG1 in 1 individual with osteopetrosis and segregated with disease in 2 affected homozygous relatives from 1 family. This variant is presumed to likely be a founder variant in the Ashkenazi Jewish population where it is estimated to have a carrier frequency of 1 in 350 (Kornak 2000 PMID: 10942435, Susani 2004 PMID: 15300850, Mazzolari 2009 PMID: 19507210, Anderson 2015 PMID: 24989235). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 5462) and has also been identified in 0.057% (2/3468) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is located in the 5' splice region. Computational tools predict and impact to splicing and in vitro functional studies using patient fibroblasts and minigene assays have shown that this variant activates an upstream cryptic splice site (also predicted by computational tools) which results in the deletion of 42 nucleotides from the transcript, resulting in the loss of 14 amino acid residues but preserving the integrity of the protein reading-frame (Kornak 2000 PMID: 10942435, Susani 2004 PMID: 15300850). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive osteopetrosis. ACMG/AMP Criteria applied: PS3_Moderate, PM3, PP1_Moderate.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.97
PhyloP100		2.0
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
Splicevardb		3.0
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.66		Position offset: -46
DS_DL_spliceai		0.50		Position offset: -4

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

Other links and lift over

dbSNP: rs751881962; hg19: chr11-67808859;