Variant 19-16680001-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_024074.4(TMEM38A):c.142C>T(p.Arg48Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000498 in 1,607,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

TMEM38A
NM_024074.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.66

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:

TMEM38A (HGNC:):

TMEM38A links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.792

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM38A	NM_024074.4 linkuse as main transcript	c.142C>T	p.Arg48Trp	missense_variant	2/6	ENST00000187762.7	NP_076979.1	Q9H6F2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM38A	ENST00000187762.7 linkuse as main transcript	c.142C>T	p.Arg48Trp	missense_variant	2/6	1	NM_024074.4	ENSP00000187762.1	Q9H6F2
TMEM38A	ENST00000599479.1 linkuse as main transcript	c.97C>T	p.Arg33Trp	missense_variant	2/4	3		ENSP00000469721.1	M0QYB6
TMEM38A	ENST00000595452.1 linkuse as main transcript	n.118C>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000481

AC:

AN:

1455042

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724076

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000211

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74444

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:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000308

Hom.:

Bravo

AF:

0.0000113

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

Sep 22, 2022

The c.142C>T (p.R48W) alteration is located in exon 2 (coding exon 2) of the TMEM38A gene. This alteration results from a C to T substitution at nucleotide position 142, causing the arginine (R) at amino acid position 48 to be replaced by a tryptophan (W). 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

0.18

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.011

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.23

Sift

Benign

0.29

Sift4G

Uncertain

0.023

Polyphen

1.0

Vest4

0.70

MutPred

0.64

Loss of solvent accessibility (P = 0.0016);

MVP

0.085

MPC

1.1

ClinPred

0.99

GERP RS

5.5

Varity_R

0.14

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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