9-105694772-G-A

Position:

chr9-105694772-G-A

Variant summary

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

The NM_018112.3(TMEM38B):c.112G>A(p.Gly38Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000085 in 1,611,224 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000089 ( 1 hom. )

Consequence

TMEM38B
NM_018112.3 missense, splice_region

Scores

Splicing: ADA: 0.9606

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.22

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:

Genome browser will be placed here

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, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM38B	NM_018112.3 linkuse as main transcript	c.112G>A	p.Gly38Arg	missense_variant, splice_region_variant	1/6	ENST00000374692.8	NP_060582.1	Q9NVV0
TMEM38B	XM_011518831.3 linkuse as main transcript	c.112G>A	p.Gly38Arg	missense_variant, splice_region_variant	1/7		XP_011517133.1
TMEM38B	XM_011518832.4 linkuse as main transcript	c.112G>A	p.Gly38Arg	missense_variant, splice_region_variant	1/4		XP_011517134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM38B	ENST00000374692.8 linkuse as main transcript	c.112G>A	p.Gly38Arg	missense_variant, splice_region_variant	1/6	1	NM_018112.3	ENSP00000363824.3	Q9NVV0
TMEM38B	ENST00000434214.1 linkuse as main transcript	c.-167G>A		splice_region_variant	1/3	2		ENSP00000403026.1	X6RGH1
TMEM38B	ENST00000434214.1 linkuse as main transcript	c.-167G>A		5_prime_UTR_variant	1/3	2		ENSP00000403026.1	X6RGH1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151918

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000170

AC:

AN:

247616

Hom.:

AF XY:

0.000223

AC XY:

AN XY:

134264

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000554

Gnomad SAS exome

AF:

0.00135

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000891

AC:

130

AN:

1459192

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

100

AN XY:

725944

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00144

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.000189

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2022

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 38 of the TMEM38B protein (p.Gly38Arg). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. This variant is present in population databases (rs551789806, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with TMEM38B-related conditions. 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.28

MutationAssessor

Pathogenic

3.1

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-6.2

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.63

MutPred

0.88

Gain of MoRF binding (P = 0.006);

MVP

0.76

MPC

0.21

ClinPred

0.49

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.80

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Pathogenic

0.82

SpliceAI score (max)

0.040

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