rs140963213

Positions:

chr11-68047516-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP3BP4_ModerateBP6BS1BS2

The NM_006019.4(TCIRG1):c.1249G>A(p.Ala417Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00378 in 1,613,942 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0039 ( 12 hom. )

Consequence

TCIRG1
NM_006019.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:3O:1

Conservation

PhyloP100: 6.59

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:

TCIRG1 (HGNC:):

TCIRG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, Dann, M_CAP, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.09511113).

BP6

Variant 11-68047516-G-A is Benign according to our data. Variant chr11-68047516-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235702.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6, not_provided=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00264 (401/152182) while in subpopulation NFE AF= 0.00403 (274/67996). AF 95% confidence interval is 0.00364. There are 2 homozygotes in gnomad4. There are 164 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCIRG1	NM_006019.4 linkuse as main transcript	c.1249G>A	p.Ala417Thr	missense_variant	11/20	ENST00000265686.8	NP_006010.2	Q13488-1A0A024R5E5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCIRG1	ENST00000265686.8 linkuse as main transcript	c.1249G>A	p.Ala417Thr	missense_variant	11/20	1	NM_006019.4	ENSP00000265686.3		Q13488-1

Frequencies

GnomAD3 genomes

AF:

0.00264

AC:

402

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00142

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00403

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00254

AC:

637

AN:

250824

Hom.:

AF XY:

0.00258

AC XY:

351

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.000989

Gnomad AMR exome

AF:

0.00234

Gnomad ASJ exome

AF:

0.00249

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.000786

Gnomad NFE exome

AF:

0.00424

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00390

AC:

5705

AN:

1461760

Hom.:

Cov.:

AF XY:

0.00381

AC XY:

2774

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.00219

Gnomad4 ASJ exome

AF:

0.00268

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00103

Gnomad4 NFE exome

AF:

0.00474

Gnomad4 OTH exome

AF:

0.00283

GnomAD4 genome

AF:

0.00264

AC:

401

AN:

152182

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

164

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00142

Gnomad4 NFE

AF:

0.00403

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00376

Hom.:

Bravo

AF:

0.00274

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00489

AC:

ExAC

AF:

0.00246

AC:

298

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00338

EpiControl

AF:

0.00462

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	TCIRG1: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 21, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TCIRG1 p.Ala201Thr variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs140963213) and in ClinVar (classified as a VUS by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics and Fulgent Genetics for Osteopetrosis autosomal recessive 1). The variant was identified in control databases in 727 of 282162 chromosomes (2 homozygous) at a frequency of 0.002577 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 548 of 128706 chromosomes (freq: 0.004258), Ashkenazi Jewish in 26 of 10332 chromosomes (freq: 0.002516), Latino in 84 of 35396 chromosomes (freq: 0.002373), Other in 15 of 7212 chromosomes (freq: 0.00208), European (Finnish) in 25 of 25086 chromosomes (freq: 0.000997), African in 22 of 24876 chromosomes (freq: 0.000884), South Asian in 6 of 30616 chromosomes (freq: 0.000196) and East Asian in 1 of 19938 chromosomes (freq: 0.00005). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Ala201 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2023	Reported with another TCIRG1 variant in two families with osteopetrosis in published literature (Afshariyamchlou et al., 2022; Jaber et al., 2022); Reported in an additional patient in published literature with severe osteopetrosis; however, further information such as zygosity or presence of another variant was not provided (Pangrazio et al., 2012); Reported in published literature in association with other phenotypes, including lower absolute neutrophil count and risk for glioma, but additional research is needed to explore a possible link between TCIRG1 variants and these phenotypes (Rosenthal et al., 2016; Kinnersley et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 34426522, 33206719, 26264438, 27229898, 35573728, 35802155, 35720663, 22231430) -

Autosomal recessive osteopetrosis 1

Uncertain:2Benign:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 08, 2020	- -

Increased bone mineral density

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2018

- -

TCIRG1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2024

The TCIRG1 c.1249G>A variant is predicted to result in the amino acid substitution p.Ala417Thr. This variant was reported in a cohort of patients with osteopetrosis; however, no additional clinical or functional information was provided to assess the pathogenicity of this variant (Pangrazio et al. 2012. PubMed ID: 22231430). In addition, this variant has been reported the compound heterozygous state with the TCIRG1 c.1735G>A (p.Gly579Arg) variant in at least three patients with osteopetrosis (Jaber et al. 2022. PubMed ID: 35802155; siblings reported in Afshariyamchlou et al. 2022. PubMed ID: 35720663).This variant is reported in 0.43% of alleles in individuals of European (Non-Finnish) descent in gnomAD including 2 homozygous inviduals which is more frequent than expected for disease-causing variants in this gene. This variant has conflicting intepretations in ClinVar ranging from uncertain to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/235702). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Neutropenia, severe congenital, 1, autosomal dominant

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Jan 02, 2024

The TCIRG1 c.1249G>A (p.Ala417Thr) missense change has a maximum subpopulation frequency of 0.43% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with autosomal recessive osteopetrosis (PMID: 22231430, 35720663, 35802155). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

D;.

Eigen

Uncertain

0.35

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.35

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.095

T;T

MetaSVM

Uncertain

0.75

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.6

D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.91

MVP

0.94

MPC

0.52

ClinPred

0.030

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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