Genetic Variant TMEM38B:p.Ala32Glu (chr9-105694755-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018112.3(TMEM38B):c.95C>A(p.Ala32Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,443,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMEM38B
NM_018112.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.15

Variant links:

Genes affected

TMEM38B (HGNC:25535): (transmembrane protein 38B) This gene encodes an intracellular monovalent cation channel that functions in maintenance of intracellular calcium release. Mutations in this gene may be associated with autosomal recessive osteogenesis. [provided by RefSeq, Oct 2012]

TMEM38B links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM38B	NM_018112.3 link	c.95C>A	p.Ala32Glu	missense_variant	Exon 1 of 6	ENST00000374692.8	NP_060582.1	Q9NVV0
TMEM38B	XM_011518831.3 link	c.95C>A	p.Ala32Glu	missense_variant	Exon 1 of 7		XP_011517133.1
TMEM38B	XM_011518832.4 link	c.95C>A	p.Ala32Glu	missense_variant	Exon 1 of 4		XP_011517134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM38B	ENST00000374692.8 link	c.95C>A	p.Ala32Glu	missense_variant	Exon 1 of 6	1	NM_018112.3	ENSP00000363824.3		Q9NVV0
TMEM38B	ENST00000434214 link	c.-184C>A		5_prime_UTR_variant	Exon 1 of 3	2		ENSP00000403026.1		X6RGH1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000804

AC:

AN:

248718

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000586

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1443942

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000454

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with glutamic acid at codon 32 of the TMEM38B protein (p.Ala32Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with TMEM38B-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.099

MetaRNN

Uncertain

0.70

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.8

REVEL

Benign

0.17

Sift

Benign

0.20

Sift4G

Uncertain

0.010

Polyphen

0.99

Vest4

0.57

MutPred

0.32

Gain of disorder (P = 0.0657);

MVP

0.62

MPC

0.28

ClinPred

0.79

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.31

gMVP

0.89

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