11-68046463-A-G

Variant names:

• chr11-68046463-A-G
• rs906713
• NM_006019.4:c.1166-970A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006019.4(TCIRG1):​c.1166-970A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.819 in 152,152 control chromosomes in the GnomAD database, including 51,025 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.82 (51025 hom., cov: 31)
• Consequence: TCIRG1 NM_006019.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.886
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 11-68046463-A-G is Benign according to our data. Variant chr11-68046463-A-G is described in ClinVar as Benign. ClinVar VariationId is 235422.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.859 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.1166-970A>G		intron	N/A	NP_006010.2
	TCIRG1	NM_001440552.1		c.1166-970A>G		intron	N/A	NP_001427481.1
	TCIRG1	NM_001440553.1		c.1166-970A>G		intron	N/A	NP_001427482.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCIRG1	ENST00000265686.8	TSL:1 MANE Select	c.1166-970A>G		intron	N/A	ENSP00000265686.3
	TCIRG1	ENST00000532635.5	TSL:1	c.518-970A>G		intron	N/A	ENSP00000434407.1
	TCIRG1	ENST00000698255.1		c.1115-970A>G		intron	N/A	ENSP00000513630.1

Frequencies

GnomAD3 genomes AF: 0.819 AC: 124470 AN: 152034 Hom.: 50988 Cov.: 31

Gnomad AFR AF: 0.789

Gnomad AMI AF: 0.841

Gnomad AMR AF: 0.872

Gnomad ASJ AF: 0.838

Gnomad EAS AF: 0.825

Gnomad SAS AF: 0.853

Gnomad FIN AF: 0.751

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.830

Gnomad OTH AF: 0.833

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.819 AC: 124560 AN: 152152 Hom.: 51025 Cov.: 31 AF XY: 0.818 AC XY: 60835 AN XY: 74356

African (AFR) AF: 0.789 AC: 32763 AN: 41504

American (AMR) AF: 0.872 AC: 13341 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.838 AC: 2911 AN: 3472

East Asian (EAS) AF: 0.825 AC: 4273 AN: 5178

South Asian (SAS) AF: 0.851 AC: 4112 AN: 4832

European-Finnish (FIN) AF: 0.751 AC: 7940 AN: 10578

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.830 AC: 56442 AN: 67972

Other (OTH) AF: 0.832 AC: 1758 AN: 2112

Alfa AF: 0.827 Hom.: 11364

Bravo AF: 0.827

Asia WGS AF: 0.830 AC: 2888 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.41
PhyloP100		-0.89
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: rs906713; hg19: chr11-67813930;