11-68049783-C-G

Variant names:

• chr11-68049783-C-G
• rs371263807
• NM_006019.4:c.2008C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006019.4(TCIRG1):​c.2008C>G​(p.Arg670Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,418,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. R670R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TCIRG1 NM_006019.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.654
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05510232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCIRG1	NM_006019.4	c.2008C>G	p.Arg670Gly	missense_variant	Exon 16 of 20	ENST00000265686.8	NP_006010.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCIRG1	ENST00000265686.8	c.2008C>G	p.Arg670Gly	missense_variant	Exon 16 of 20	1	NM_006019.4	ENSP00000265686.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000141 AC: 20 AN: 1418152 Hom.: 0 Cov.: 33 AF XY: 0.0000128 AC XY: 9 AN XY: 703022

African (AFR) AF: 0.00 AC: 0 AN: 33136

American (AMR) AF: 0.00 AC: 0 AN: 38752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25414

East Asian (EAS) AF: 0.00 AC: 0 AN: 38594

South Asian (SAS) AF: 0.00 AC: 0 AN: 82224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4170

European-Non Finnish (NFE) AF: 0.0000182 AC: 20 AN: 1097262

Other (OTH) AF: 0.00 AC: 0 AN: 59064

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive osteopetrosis 1 Uncertain:1

Feb 18, 2025

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	1.8
DANN	Benign	0.42
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.055	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	-0.52	N;.
PhyloP100		-0.65
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.18	N;N
REVEL	Benign	0.14
Sift	Benign	0.56	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.0	B;.
Vest4		0.077
MutPred		0.43		Loss of solvent accessibility (P = 0.0146);.;
MVP		0.25
MPC		0.20
ClinPred		0.017	T
GERP RS		-3.2
PromoterAI		0.0018	Neutral
Varity_R		0.053
gMVP		0.34
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs371263807; hg19: chr11-67817250;