Variant 3-12743923-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018306.4(TMEM40):c.278A>G(p.Tyr93Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,850 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TMEM40
NM_018306.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.49

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.046159476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM40	NM_018306.4 linkuse as main transcript	c.278A>G	p.Tyr93Cys	missense_variant	4/12	ENST00000314124.12	NP_060776.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM40	ENST00000314124.12 linkuse as main transcript	c.278A>G	p.Tyr93Cys	missense_variant	4/12	2	NM_018306.4	ENSP00000322837	A2	Q8WWA1-1
TMEM40	ENST00000435218.6 linkuse as main transcript	c.212-1416A>G		intron_variant		1		ENSP00000405740	P2	Q8WWA1-2
TMEM40	ENST00000264728.8 linkuse as main transcript	c.278A>G	p.Tyr93Cys	missense_variant	4/12	2		ENSP00000264728	A2	Q8WWA1-1
TMEM40	ENST00000435575.5 linkuse as main transcript	c.74-1416A>G		intron_variant		2		ENSP00000396895		Q8WWA1-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250338

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135278

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:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460850

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726602

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:

0.0000816

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

The c.278A>G (p.Y93C) alteration is located in exon 4 (coding exon 3) of the TMEM40 gene. This alteration results from a A to G substitution at nucleotide position 278, causing the tyrosine (Y) at amino acid position 93 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.52

CADD

Benign

5.2

DANN

Benign

0.36

DEOGEN2

Benign

0.0042

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.43

.;T

M_CAP

Benign

0.0017

MetaRNN

Benign

0.046

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.040

Sift

Benign

0.061

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.19

B;B

Vest4

0.23

MVP

0.014

MPC

0.010

ClinPred

0.16

GERP RS

-3.6

Varity_R

0.056

gMVP

0.045

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