chr11-68041801-C-T

Position:

chr11-68041801-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000265686.8(TCIRG1):c.166C>T(p.Arg56Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0527 in 1,609,634 control chromosomes in the GnomAD database, including 2,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R56Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.041 ( 174 hom., cov: 33)

Exomes 𝑓: 0.054 ( 2399 hom. )

Consequence

TCIRG1
ENST00000265686.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.32

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0089764595).

BP6

Variant 11-68041801-C-T is Benign according to our data. Variant chr11-68041801-C-T is described in ClinVar as [Benign]. Clinvar id is 305782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68041801-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.057 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCIRG1	NM_006019.4 linkuse as main transcript	c.166C>T	p.Arg56Trp	missense_variant	3/20	ENST00000265686.8	NP_006010.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCIRG1	ENST00000265686.8 linkuse as main transcript	c.166C>T	p.Arg56Trp	missense_variant	3/20	1	NM_006019.4	ENSP00000265686	P1	Q13488-1

Frequencies

GnomAD3 genomes

AF:

0.0411

AC:

6256

AN:

152146

Hom.:

174

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0106

Gnomad AMI

AF:

0.0352

Gnomad AMR

AF:

0.0336

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0174

Gnomad FIN

AF:

0.0627

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0585

Gnomad OTH

AF:

0.0474

GnomAD3 exomes

AF:

0.0462

AC:

11186

AN:

242334

Hom.:

396

AF XY:

0.0472

AC XY:

6190

AN XY:

131244

show subpopulations

Gnomad AFR exome

AF:

0.00717

Gnomad AMR exome

AF:

0.0286

Gnomad ASJ exome

AF:

0.117

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.0170

Gnomad FIN exome

AF:

0.0678

Gnomad NFE exome

AF:

0.0617

Gnomad OTH exome

AF:

0.0528

GnomAD4 exome

AF:

0.0539

AC:

78531

AN:

1457370

Hom.:

2399

Cov.:

AF XY:

0.0533

AC XY:

38637

AN XY:

724476

show subpopulations

Gnomad4 AFR exome

AF:

0.00766

Gnomad4 AMR exome

AF:

0.0300

Gnomad4 ASJ exome

AF:

0.114

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.0181

Gnomad4 FIN exome

AF:

0.0701

Gnomad4 NFE exome

AF:

0.0586

Gnomad4 OTH exome

AF:

0.0544

GnomAD4 genome

AF:

0.0411

AC:

6254

AN:

152264

Hom.:

174

Cov.:

AF XY:

0.0404

AC XY:

3008

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0106

Gnomad4 AMR

AF:

0.0335

Gnomad4 ASJ

AF:

0.119

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0178

Gnomad4 FIN

AF:

0.0627

Gnomad4 NFE

AF:

0.0585

Gnomad4 OTH

AF:

0.0469

Alfa

AF:

0.0591

Hom.:

503

Bravo

AF:

0.0390

TwinsUK

AF:

0.0553

AC:

205

ALSPAC

AF:

0.0594

AC:

229

ESP6500AA

AF:

0.0100

AC:

ESP6500EA

AF:

0.0637

AC:

547

ExAC

AF:

0.0448

AC:

5426

Asia WGS

AF:

0.00924

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive osteopetrosis 1

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified

Benign:2

Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Increased bone mineral density

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 10, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;D;D

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D;D

MetaRNN

Benign

0.0090

T;T;T

MetaSVM

Uncertain

0.062

MutationAssessor

Pathogenic

3.6

H;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.4

D;D;D

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.23

MPC

0.67

ClinPred

0.11

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.68

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over