rs201972729

Variant names:

• chr11-68041279-C-A
• rs201972729
• NM_006019.4:c.8C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-68041279-C-A
• chr11-68041279-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006019.4(TCIRG1):​c.8C>A​(p.Ser3Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,224 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S3F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TCIRG1 NM_006019.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.55
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCIRG1	NM_006019.4	MANE Select	c.8C>A	p.Ser3Tyr	missense	Exon 2 of 20	NP_006010.2
	TCIRG1	NM_001440552.1		c.8C>A	p.Ser3Tyr	missense	Exon 3 of 21	NP_001427481.1
	TCIRG1	NM_001440553.1		c.8C>A	p.Ser3Tyr	missense	Exon 2 of 20	NP_001427482.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCIRG1	ENST00000265686.8	TSL:1 MANE Select	c.8C>A	p.Ser3Tyr	missense	Exon 2 of 20	ENSP00000265686.3	Q13488-1
	TCIRG1	ENST00000698255.1		c.8C>A	p.Ser3Tyr	missense	Exon 2 of 20	ENSP00000513630.1	A0A8V8TM28
	TCIRG1	ENST00000698254.1		c.8C>A	p.Ser3Tyr	missense	Exon 2 of 16	ENSP00000513629.1	A0A8V8TN16

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460224 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726448

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111486

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.31		Loss of disorder (P = 0.036)
MVP		0.97
MPC		0.68
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.82
gMVP		0.56
Mutation Taster		=41/59	disease causing

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: rs201972729; hg19: chr11-67808746;