Variant chr8-124313964-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The ENST00000297632.8(TMEM65):c.719G>A(p.Ser240Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000392 in 1,608,860 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 1 hom. )

Consequence

TMEM65
ENST00000297632.8 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.81

Variant links:

Genes affected

TMEM65 (HGNC:25203): (transmembrane protein 65) Predicted to be involved in cardiac ventricle development and regulation of cardiac conduction. Located in intercalated disc; mitochondrial inner membrane; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM65 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.026211947).

BP6

Variant 8-124313964-C-T is Benign according to our data. Variant chr8-124313964-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2590980.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM65	NM_194291.3 linkuse as main transcript	c.719G>A	p.Ser240Asn	missense_variant	7/7	ENST00000297632.8	NP_919267.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM65	ENST00000297632.8 linkuse as main transcript	c.719G>A	p.Ser240Asn	missense_variant	7/7	1	NM_194291.3	ENSP00000297632	P1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000363

AC:

AN:

247674

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134154

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000632

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000371

AC:

AN:

1456772

Hom.:

Cov.:

AF XY:

0.0000345

AC XY:

AN XY:

724982

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000460

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000387

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000594

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.22

DEOGEN2

Benign

0.0088

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.60

M_CAP

Benign

0.0054

MetaRNN

Benign

0.026

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.3

MutationTaster

Benign

1.0

PrimateAI

Benign

0.41

PROVEAN

Benign

0.47

REVEL

Benign

0.079

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.13

MVP

0.043

MPC

0.81

ClinPred

0.025

GERP RS

4.6

Varity_R

0.038

gMVP

0.22

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

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