11-68047512-G-C

Variant names:

• chr11-68047512-G-C
• rs2471829
• NM_006019.4:c.1245G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006019.4(TCIRG1):​c.1245G>C​(p.Leu415Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,614,050 control chromosomes in the GnomAD database, including 800,157 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L415L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.98 (72930 hom., cov: 31)
  • Exomes 𝑓: 1.0 (727227 hom.)
• Consequence: TCIRG1 NM_006019.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.330
• Publications: 20 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.062).
• BP6: Variant 11-68047512-G-C is Benign according to our data. Variant chr11-68047512-G-C is described in ClinVar as Benign. ClinVar VariationId is 235632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006019.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCIRG1	NM_006019.4	MANE Select	c.1245G>C	p.Leu415Leu	synonymous	Exon 11 of 20	NP_006010.2
	TCIRG1	NM_001440552.1		c.1245G>C	p.Leu415Leu	synonymous	Exon 12 of 21	NP_001427481.1
	TCIRG1	NM_001440553.1		c.1245G>C	p.Leu415Leu	synonymous	Exon 11 of 20	NP_001427482.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCIRG1	ENST00000265686.8	TSL:1 MANE Select	c.1245G>C	p.Leu415Leu	synonymous	Exon 11 of 20	ENSP00000265686.3
	TCIRG1	ENST00000532635.5	TSL:1	c.597G>C	p.Leu199Leu	synonymous	Exon 6 of 15	ENSP00000434407.1
	TCIRG1	ENST00000529364.1	TSL:3	c.655G>C	p.Val219Leu	missense	Exon 6 of 7	ENSP00000431437.1

Frequencies

GnomAD3 genomes AF: 0.978 AC: 148813 AN: 152142 Hom.: 72872 Cov.: 31

Gnomad AFR AF: 0.924

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.992

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.981

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.986

GnomAD2 exomes AF: 0.994 AC: 249461 AN: 250922 AF XY: 0.996

Gnomad AFR exome AF: 0.923

Gnomad AMR exome AF: 0.996

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.996

GnomAD4 exome AF: 0.997 AC: 1457975 AN: 1461790 Hom.: 727227 Cov.: 67 AF XY: 0.998 AC XY: 725561 AN XY: 727198

African (AFR) AF: 0.914 AC: 30604 AN: 33480

American (AMR) AF: 0.996 AC: 44525 AN: 44716

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26134 AN: 26134

East Asian (EAS) AF: 1.00 AC: 39700 AN: 39700

South Asian (SAS) AF: 1.00 AC: 86247 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 53333 AN: 53340

Middle Eastern (MID) AF: 0.992 AC: 5719 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111639 AN: 1112000

Other (OTH) AF: 0.995 AC: 60074 AN: 60394

GnomAD4 genome AF: 0.978 AC: 148929 AN: 152260 Hom.: 72930 Cov.: 31 AF XY: 0.979 AC XY: 72882 AN XY: 74472

African (AFR) AF: 0.924 AC: 38371 AN: 41520

American (AMR) AF: 0.992 AC: 15182 AN: 15300

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5171 AN: 5172

South Asian (SAS) AF: 1.00 AC: 4832 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10628 AN: 10628

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67989 AN: 68016

Other (OTH) AF: 0.986 AC: 2084 AN: 2114

Alfa AF: 0.952 Hom.: 21845

Bravo AF: 0.975

Asia WGS AF: 0.994 AC: 3457 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

Jan 24, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: MAF

Autosomal recessive osteopetrosis 1 Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.8
DANN	Benign	0.95
PhyloP100		0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2471829; hg19: chr11-67814979; COSMIC: COSV108104909; COSMIC: COSV108104909;