Variant chr3-12748730-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 NM_018306.4(TMEM40):c.136G>A(p.Glu46Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

TMEM40
NM_018306.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.632

Variant links:

Genes affected

TMEM40 (HGNC:25620): (transmembrane protein 40) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM40 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=0.021512836).

BP6

Variant 3-12748730-C-T is Benign according to our data. Variant chr3-12748730-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2358958.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM40	NM_018306.4 linkuse as main transcript	c.136G>A	p.Glu46Lys	missense_variant	3/12	ENST00000314124.12	NP_060776.2	Q8WWA1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM40	ENST00000314124.12 linkuse as main transcript	c.136G>A	p.Glu46Lys	missense_variant	3/12	2	NM_018306.4	ENSP00000322837.7	Q8WWA1-1
TMEM40	ENST00000435218.6 linkuse as main transcript	c.136G>A	p.Glu46Lys	missense_variant	3/11	1		ENSP00000405740.2	Q8WWA1-2
TMEM40	ENST00000264728.8 linkuse as main transcript	c.136G>A	p.Glu46Lys	missense_variant	3/12	2		ENSP00000264728.8	Q8WWA1-1
TMEM40	ENST00000435575.5 linkuse as main transcript	c.73+1030G>A		intron_variant		2		ENSP00000396895.1	Q8WWA1-3

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.000368

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000100

AC:

AN:

249042

Hom.:

AF XY:

0.0000816

AC XY:

AN XY:

134816

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000225

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000278

AC:

406

AN:

1461852

Hom.:

Cov.:

AF XY:

0.000250

AC XY:

182

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.000359

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000197

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000120

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:

0.000368

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000258

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

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

Jan 04, 2022

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

0.065

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.86

DANN

Benign

0.64

DEOGEN2

Benign

0.010

T;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0064

LIST_S2

Benign

0.71

.;T;T

M_CAP

Benign

0.0015

MetaRNN

Benign

0.022

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.11

N;N;N

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.82

N;N;N

REVEL

Benign

0.0060

Sift

Benign

0.40

T;T;T

Sift4G

Benign

0.77

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.15

MVP

0.014

MPC

0.011

ClinPred

0.011

GERP RS

-1.4

Varity_R

0.037

gMVP

0.074

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