Genetic Variant TMEM247:p.Glu57Gln (chr2-46480456-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001424184.1(TMEM247):c.169G>C(p.Glu57Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0027 in 1,551,598 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 7 hom. )

Consequence

TMEM247
NM_001424184.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.02

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060884953).

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM247	NM_001424184.1 link	c.169G>C	p.Glu57Gln	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.169G>C	p.Glu57Gln	missense_variant	Exon 2 of 3	5	ENSP00000388684.1	A6NEH6
ENSG00000284608	ENST00000432241.5 link	n.365-3788G>C		intron_variant	Intron 4 of 4	3
ENSG00000253515	ENST00000517716.2 link	n.80-19275G>C		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.00285

AC:

433

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00881

Gnomad AMR

AF:

0.00667

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00357

Gnomad OTH

AF:

0.00716

GnomAD3 exomes

AF:

0.00209

AC:

326

AN:

156224

Hom.:

AF XY:

0.00194

AC XY:

161

AN XY:

82826

show subpopulations

Gnomad AFR exome

AF:

0.00114

Gnomad AMR exome

AF:

0.00405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000439

Gnomad FIN exome

AF:

0.000717

Gnomad NFE exome

AF:

0.00300

Gnomad OTH exome

AF:

0.00319

GnomAD4 exome

AF:

0.00268

AC:

3749

AN:

1399288

Hom.:

Cov.:

AF XY:

0.00261

AC XY:

1803

AN XY:

690152

show subpopulations

Gnomad4 AFR exome

AF:

0.000886

Gnomad4 AMR exome

AF:

0.00392

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000480

Gnomad4 FIN exome

AF:

0.000549

Gnomad4 NFE exome

AF:

0.00308

Gnomad4 OTH exome

AF:

0.00314

GnomAD4 genome

AF:

0.00284

AC:

433

AN:

152310

Hom.:

Cov.:

AF XY:

0.00287

AC XY:

214

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00115

Gnomad4 AMR

AF:

0.00666

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00357

Gnomad4 OTH

AF:

0.00709

Alfa

AF:

0.00306

Hom.:

Bravo

AF:

0.00281

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00311

AC:

ExAC

AF:

0.000861

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.169G>C (p.E57Q) alteration is located in exon 2 (coding exon 2) of the TMEM247 gene. This alteration results from a G to C substitution at nucleotide position 169, causing the glutamic acid (E) at amino acid position 57 to be replaced by a glutamine (Q). 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

0.19

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

Eigen

Benign

0.0074

Eigen_PC

Benign

0.016

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0061

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.2

PROVEAN

Benign

-1.8

REVEL

Benign

0.16

Sift

Benign

0.12

Sift4G

Benign

0.22

Polyphen

0.72

MVP

0.048

ClinPred

0.084

GERP RS

4.8

Varity_R

0.14

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