rs1208311085

Variant names:

• chr11-68042683-GCCCC-G
• rs1208311085
• NM_006019.4:c.239_242delCCCC

Your query was ambiguous. Multiple possible variants found:

• chr11-68042683-GCCCC-G
• chr11-68042683-GCCCC-GCCC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_006019.4(TCIRG1):​c.239_242delCCCC​(p.Pro80ArgfsTer85) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,172 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P80P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TCIRG1 NM_006019.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.900
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCIRG1	NM_006019.4	c.239_242delCCCC	p.Pro80ArgfsTer85	frameshift_variant	Exon 4 of 20	ENST00000265686.8	NP_006010.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCIRG1	ENST00000265686.8	c.239_242delCCCC	p.Pro80ArgfsTer85	frameshift_variant	Exon 4 of 20	1	NM_006019.4	ENSP00000265686.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000717 AC: 1 AN: 139554 AF XY: 0.0000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394172 Hom.: 0 AF XY: 0.00000145 AC XY: 1 AN XY: 687488

African (AFR) AF: 0.00 AC: 0 AN: 31480

American (AMR) AF: 0.00 AC: 0 AN: 35570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25056

East Asian (EAS) AF: 0.00 AC: 0 AN: 35704

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 79012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4074

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077992

Other (OTH) AF: 0.00 AC: 0 AN: 57728

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.90
Mutation Taster		=24/176	disease causing (fs/PTC)

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: rs1208311085; hg19: chr11-67810150;