rs3808974

Variant names:

• chr11-68042874-A-G
• rs3808974
• NM_006019.4:c.417+11A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-68042874-A-G
• chr11-68042874-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006019.4(TCIRG1):​c.417+11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 1,549,548 control chromosomes in the GnomAD database, including 58,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8480 hom., cov: 34)
  • Exomes 𝑓: 0.26 (50216 hom.)
• Consequence: TCIRG1 NM_006019.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.153
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-68042874-A-G is Benign according to our data. Variant chr11-68042874-A-G is described in ClinVar as Benign. ClinVar VariationId is 197264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCIRG1	NM_006019.4	c.417+11A>G		intron_variant	Intron 4 of 19	ENST00000265686.8	NP_006010.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCIRG1	ENST00000265686.8	c.417+11A>G		intron_variant	Intron 4 of 19	1	NM_006019.4	ENSP00000265686.3

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48334 AN: 151868 Hom.: 8466 Cov.: 34

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.289

GnomAD2 exomes AF: 0.245 AC: 36770 AN: 149916 AF XY: 0.241

Gnomad AFR exome AF: 0.489

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.232

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.260

GnomAD4 exome AF: 0.264 AC: 369545 AN: 1397562 Hom.: 50216 Cov.: 40 AF XY: 0.262 AC XY: 180646 AN XY: 689270

African (AFR) AF: 0.485 AC: 15310 AN: 31578

American (AMR) AF: 0.203 AC: 7233 AN: 35676

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 6142 AN: 25156

East Asian (EAS) AF: 0.263 AC: 9380 AN: 35732

South Asian (SAS) AF: 0.180 AC: 14272 AN: 79236

European-Finnish (FIN) AF: 0.224 AC: 10743 AN: 48052

Middle Eastern (MID) AF: 0.253 AC: 1409 AN: 5568

European-Non Finnish (NFE) AF: 0.269 AC: 289773 AN: 1078648

Other (OTH) AF: 0.264 AC: 15283 AN: 57916

GnomAD4 genome AF: 0.318 AC: 48396 AN: 151986 Hom.: 8480 Cov.: 34 AF XY: 0.314 AC XY: 23294 AN XY: 74280

African (AFR) AF: 0.476 AC: 19736 AN: 41480

American (AMR) AF: 0.249 AC: 3816 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 802 AN: 3472

East Asian (EAS) AF: 0.245 AC: 1255 AN: 5114

South Asian (SAS) AF: 0.175 AC: 844 AN: 4828

European-Finnish (FIN) AF: 0.216 AC: 2285 AN: 10568

Middle Eastern (MID) AF: 0.195 AC: 57 AN: 292

European-Non Finnish (NFE) AF: 0.275 AC: 18687 AN: 67910

Other (OTH) AF: 0.286 AC: 604 AN: 2112

Alfa AF: 0.286 Hom.: 1418

Bravo AF: 0.325

Asia WGS AF: 0.233 AC: 812 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Nov 23, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive osteopetrosis 1 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.4
DANN	Benign	0.64
PhyloP100		-0.15
PromoterAI		-0.011	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs3808974; hg19: chr11-67810341; COSMIC: COSV55836540; COSMIC: COSV55836540;