Variant 15-81332588-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1BS2

The NM_001080532.3(TMC3):c.3134C>A(p.Ser1045*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0178 in 1,613,954 control chromosomes in the GnomAD database, including 304 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 23 hom., cov: 32)

Exomes 𝑓: 0.018 ( 281 hom. )

Consequence

TMC3
NM_001080532.3 stop_gained

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 8.97

Variant links:

Genes affected

TMC3 (HGNC:22995): (transmembrane channel like 3) Predicted to enable mechanosensitive ion channel activity. Predicted to be involved in ion transmembrane transport. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMC3 links:

TMC3-AS1 (HGNC:):

TMC3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.014 (2135/152302) while in subpopulation AMR AF= 0.0243 (372/15302). AF 95% confidence interval is 0.0223. There are 23 homozygotes in gnomad4. There are 1011 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC3	NM_001080532.3 linkuse as main transcript	c.3134C>A	p.Ser1045*	stop_gained	22/22	ENST00000359440.6	NP_001074001.1	Q7Z5M5-1
TMC3-AS1	NR_120365.1 linkuse as main transcript	n.426+47G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC3	ENST00000359440.6 linkuse as main transcript	c.3134C>A	p.Ser1045*	stop_gained	22/22	1	NM_001080532.3	ENSP00000352413.5		Q7Z5M5-1

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

2135

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00475

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0243

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0211

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0126

AC:

3137

AN:

249090

Hom.:

AF XY:

0.0127

AC XY:

1716

AN XY:

135132

show subpopulations

Gnomad AFR exome

AF:

0.00446

Gnomad AMR exome

AF:

0.0138

Gnomad ASJ exome

AF:

0.0123

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00298

Gnomad FIN exome

AF:

0.00172

Gnomad NFE exome

AF:

0.0196

Gnomad OTH exome

AF:

0.0207

GnomAD4 exome

AF:

0.0182

AC:

26570

AN:

1461652

Hom.:

281

Cov.:

AF XY:

0.0177

AC XY:

12893

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.00421

Gnomad4 AMR exome

AF:

0.0144

Gnomad4 ASJ exome

AF:

0.0123

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00325

Gnomad4 FIN exome

AF:

0.00202

Gnomad4 NFE exome

AF:

0.0216

Gnomad4 OTH exome

AF:

0.0158

GnomAD4 genome

AF:

0.0140

AC:

2135

AN:

152302

Hom.:

Cov.:

AF XY:

0.0136

AC XY:

1011

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00474

Gnomad4 AMR

AF:

0.0243

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.00170

Gnomad4 NFE

AF:

0.0211

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0188

Hom.:

Bravo

AF:

0.0154

TwinsUK

AF:

0.0210

AC:

ALSPAC

AF:

0.0176

AC:

ESP6500AA

AF:

0.00490

AC:

ESP6500EA

AF:

0.0214

AC:

182

ExAC

AF:

0.0120

AC:

1458

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0243

EpiControl

AF:

0.0254

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Nov 06, 2015

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

Vest4

0.13

GERP RS

5.2

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

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