chr9-105694703-A-C

Position:

chr9-105694703-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018112.3(TMEM38B):c.43A>C(p.Thr15Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000433 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

TMEM38B
NM_018112.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 1.16

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21303385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM38B	NM_018112.3 linkuse as main transcript	c.43A>C	p.Thr15Pro	missense_variant	1/6	ENST00000374692.8	NP_060582.1	Q9NVV0
TMEM38B	XM_011518831.3 linkuse as main transcript	c.43A>C	p.Thr15Pro	missense_variant	1/7		XP_011517133.1
TMEM38B	XM_011518832.4 linkuse as main transcript	c.43A>C	p.Thr15Pro	missense_variant	1/4		XP_011517134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM38B	ENST00000374692.8 linkuse as main transcript	c.43A>C	p.Thr15Pro	missense_variant	1/6	1	NM_018112.3	ENSP00000363824.3		Q9NVV0
TMEM38B	ENST00000434214.1 linkuse as main transcript	c.-236A>C		5_prime_UTR_variant	1/3	2		ENSP00000403026.1		X6RGH1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000243

AC:

AN:

250960

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135796

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:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000503

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000458

AC:

670

AN:

1461690

Hom.:

Cov.:

AF XY:

0.000421

AC XY:

306

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000574

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000191

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000454

Hom.:

Bravo

AF:

0.000178

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2022	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 15 of the TMEM38B protein (p.Thr15Pro). This variant is present in population databases (rs138722007, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with TMEM38B-related conditions. ClinVar contains an entry for this variant (Variation ID: 1050400). 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"). 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TMEM38B p.T15P variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs138722007) and in control databases in 66 of 282248 chromosomes at a frequency of 0.0002338 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 61 of 128700 chromosomes (freq: 0.000474), European (Finnish) in 4 of 25092 chromosomes (freq: 0.000159) and Other in 1 of 7212 chromosomes (freq: 0.000139), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, or South Asian populations. The p.T15 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Benign

-0.0097

Eigen_PC

Benign

-0.0063

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.56

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.21

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.9

REVEL

Benign

0.15

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.019

Polyphen

0.95

Vest4

0.42

MVP

0.30

MPC

0.18

ClinPred

0.14

GERP RS

3.0

Varity_R

0.30

gMVP

0.68

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