Variant 19-16688273-G-A 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_024074.4(TMEM38A):c.802G>A(p.Gly268Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000852 in 1,607,762 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: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

TMEM38A
NM_024074.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.98

Variant links:

Genes affected

TMEM38A (HGNC:28462): (transmembrane protein 38A) Predicted to enable potassium channel activity. Predicted to act upstream of or within several processes, including cellular response to caffeine; inorganic cation transmembrane transport; and regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

TMEM38A links:

Genome browser will be placed here

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=0.027835727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM38A	NM_024074.4 linkuse as main transcript	c.802G>A	p.Gly268Ser	missense_variant	6/6	ENST00000187762.7	NP_076979.1	Q9H6F2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM38A	ENST00000187762.7 linkuse as main transcript	c.802G>A	p.Gly268Ser	missense_variant	6/6	1	NM_024074.4	ENSP00000187762.1		Q9H6F2
TMEM38A	ENST00000599479.1 linkuse as main transcript	c.325-650G>A		intron_variant		3		ENSP00000469721.1		M0QYB6

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000905

AC:

AN:

243030

Hom.:

AF XY:

0.0000684

AC XY:

AN XY:

131668

show subpopulations

Gnomad AFR exome

AF:

0.0000632

Gnomad AMR exome

AF:

0.0000912

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000569

Gnomad SAS exome

AF:

0.0000336

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000547

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.0000879

AC:

128

AN:

1455446

Hom.:

Cov.:

AF XY:

0.0000967

AC XY:

AN XY:

723934

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000683

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.000154

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000992

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000824

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

Dec 19, 2022

The c.802G>A (p.G268S) alteration is located in exon 6 (coding exon 6) of the TMEM38A gene. This alteration results from a G to A substitution at nucleotide position 802, causing the glycine (G) at amino acid position 268 to be replaced by a serine (S). 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

0.069

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.45

CADD

Benign

6.1

DANN

Benign

0.54

DEOGEN2

Benign

0.012

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.53

M_CAP

Benign

0.0015

MetaRNN

Benign

0.028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.32

PROVEAN

Benign

0.49

REVEL

Benign

0.066

Sift

Benign

0.58

Sift4G

Benign

0.79

Polyphen

0.31

Vest4

0.18

MutPred

0.095

Gain of glycosylation at G268 (P = 0.0016);

MVP

0.014

MPC

0.33

ClinPred

0.0099

GERP RS

0.80

Varity_R

0.031

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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