rs199973759

chr11-68050524-A-AGGCCTGchr11-68050524-A-AGGCCTGGGCCTG

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_006019.4(TCIRG1):c.2285_2290dup(p.Leu762_Gly763dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.00361 in 1,613,774 control chromosomes in the GnomAD database, including 196 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I758I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (101 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (95 hom.)
• Consequence: TCIRG1 NM_006019.4 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.46

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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_006019.4
• BP6: Variant 11-68050524-A-AGGCCTG is Benign according to our data. Variant chr11-68050524-A-AGGCCTG is described in ClinVar as [Likely_benign]. Clinvar id is 305820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCIRG1	NM_006019.4	c.2285_2290dup	p.Leu762_Gly763dup	inframe_insertion	19/20	ENST00000265686.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCIRG1	ENST00000265686.8	c.2285_2290dup	p.Leu762_Gly763dup	inframe_insertion	19/20	1	NM_006019.4	P1

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2954 AN: 152188 Hom.: 101 Cov.: 33

Gnomad AFR AF: 0.0671

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00765

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.00509 AC: 1278 AN: 251248 Hom.: 34 AF XY: 0.00391 AC XY: 531 AN XY: 135850

Gnomad AFR exome AF: 0.0688

Gnomad AMR exome AF: 0.00333

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00196 AC: 2864 AN: 1461468 Hom.: 95 Cov.: 33 AF XY: 0.00168 AC XY: 1222 AN XY: 727064

Gnomad4 AFR exome AF: 0.0681

Gnomad4 AMR exome AF: 0.00369

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.00450

GnomAD4 genome AF: 0.0194 AC: 2956 AN: 152306 Hom.: 101 Cov.: 33 AF XY: 0.0183 AC XY: 1364 AN XY: 74468

Gnomad4 AFR AF: 0.0670

Gnomad4 AMR AF: 0.00764

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.0217

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Osteopetrosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199973759; hg19: chr11-67817991;