11-68041392-A-T

Position:

chr11-68041392-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_006019.4(TCIRG1):c.117+4A>T variant causes a splice donor 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. 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_donor_region, intron

Scores

Splicing: ADA: 0.9991

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 1.98

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 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius 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 [Likely_pathogenic]. Clinvar id is 5462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCIRG1	NM_006019.4 linkuse as main transcript	c.117+4A>T		splice_donor_region_variant, intron_variant		ENST00000265686.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCIRG1	ENST00000265686.8 linkuse as main transcript	c.117+4A>T		splice_donor_region_variant, intron_variant		1	NM_006019.4	P1	Q13488-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152030

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000443

AC:

AN:

248134

Hom.:

AF XY:

0.0000520

AC XY:

AN XY:

134612

show subpopulations

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 SAS 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:

AN:

1451214

Hom.:

Cov.:

AF XY:

0.0000402

AC XY:

AN XY:

721898

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00134

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000997

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000677

Hom.:

Bravo

AF:

0.0000453

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive osteopetrosis 1

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 15, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 12, 2000	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	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 -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2020	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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2022

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. -

Autosomal recessive osteopetrosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 28, 2023

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

DANN

Benign

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

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

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