Genetic Variant TMEM247:p.Arg158Cys (chr2-46480759-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001424184.1(TMEM247):c.472C>T(p.Arg158Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000978 in 1,125,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000015 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

TMEM247
NM_001424184.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.681

Variant links:

Genes affected

TMEM247 (HGNC:42967): (transmembrane protein 247) Predicted to be integral component of membrane. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

TMEM247 links:

ENSG00000284608 (HGNC:):

ENSG00000284608 links:

Genome browser will be placed here

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=0.10819399).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM247	NM_001424184.1 link	c.472C>T	p.Arg158Cys	missense_variant	Exon 2 of 3		NP_001411113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
TMEM247	ENST00000434431.2 link	c.472C>T	p.Arg158Cys	missense_variant	Exon 2 of 3	5	ENSP00000388684.1	A6NEH6
ENSG00000284608	ENST00000432241.5 link	n.365-3485C>T		intron_variant	Intron 4 of 4	3
ENSG00000253515	ENST00000517716.2 link	n.80-18972C>T		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.0000153

AC:

AN:

65488

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000687

AC:

AN:

145644

Hom.:

AF XY:

0.0000129

AC XY:

AN XY:

77768

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:

0.00

Gnomad NFE exome

AF:

0.0000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000944

AC:

AN:

1059662

Hom.:

Cov.:

AF XY:

0.0000118

AC XY:

AN XY:

507556

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000113

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000153

AC:

AN:

65488

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

31678

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:

0.0000375

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000645

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.472C>T (p.R158C) alteration is located in exon 2 (coding exon 2) of the TMEM247 gene. This alteration results from a C to T substitution at nucleotide position 472, causing the arginine (R) at amino acid position 158 to be replaced by a cysteine (C). 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

0.11

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.052

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.51

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PROVEAN

Pathogenic

-4.6

REVEL

Benign

0.14

Sift

Uncertain

0.0020

Sift4G

Benign

0.085

Polyphen

0.015

MutPred

0.31

Gain of catalytic residue at P157 (P = 0.0086);

MVP

0.10

ClinPred

0.18

GERP RS

3.9

Varity_R

0.084

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