rs3808974

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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:5
• Conservation: PhyloP100: -0.153

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
TCIRG1	NM_006019.4	c.417+11A>G		intron_variant		ENST00000265686.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCIRG1	ENST00000265686.8	c.417+11A>G		intron_variant		1	NM_006019.4	P1

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

GnomAD3 exomes AF: 0.245 AC: 36770 AN: 149916 Hom.: 4811 AF XY: 0.241 AC XY: 19396 AN XY: 80338

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 SAS exome AF: 0.183

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

Gnomad4 AFR exome AF: 0.485

Gnomad4 AMR exome AF: 0.203

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.263

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.224

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.264

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

Gnomad4 AFR AF: 0.476

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.245

Gnomad4 SAS AF: 0.175

Gnomad4 FIN AF: 0.216

Gnomad4 NFE AF: 0.275

Gnomad4 OTH AF: 0.286

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 23, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -

Autosomal recessive osteopetrosis 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.4
DANN	Benign	0.64

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

Publications

LitVar

Other links and lift over

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