Genetic Variant TMEM247:p.Glu114Lys (chr2-46480627-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP4

The NM_001424184.1(TMEM247):c.340G>A(p.Glu114Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000932 in 1,395,362 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 0.000039 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

TMEM247
NM_001424184.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.18

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 4: AlphaMissense, BayesDel_noAF, Cadd, Dann [when max_spliceai, MetaRNN was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.41418323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM247	NM_001424184.1 link	c.340G>A	p.Glu114Lys	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.340G>A	p.Glu114Lys	missense_variant	Exon 2 of 3	5	ENSP00000388684.1	A6NEH6
ENSG00000284608	ENST00000432241.5 link	n.365-3617G>A		intron_variant	Intron 4 of 4	3
ENSG00000253515	ENST00000517716.2 link	n.80-19104G>A		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

101208

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:

0.000818

Gnomad SAS

AF:

0.000666

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000129

AC:

AN:

155030

Hom.:

AF XY:

0.0000122

AC XY:

AN XY:

82284

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000184

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:

0.00000695

AC:

AN:

1294040

Hom.:

Cov.:

AF XY:

0.00000785

AC XY:

AN XY:

636786

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000132

Gnomad4 SAS exome

AF:

0.0000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000493

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000395

AC:

AN:

101322

Hom.:

Cov.:

AF XY:

0.0000204

AC XY:

AN XY:

49020

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000820

Gnomad4 SAS

AF:

0.000665

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.340G>A (p.E114K) alteration is located in exon 2 (coding exon 2) of the TMEM247 gene. This alteration results from a G to A substitution at nucleotide position 340, causing the glutamic acid (E) at amino acid position 114 to be replaced by a lysine (K). 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

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.84

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.4

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.34

Sift

Benign

0.090

Sift4G

Benign

0.087

Polyphen

1.0

MutPred

0.23

Gain of MoRF binding (P = 0.0081);

MVP

0.085

ClinPred

0.95

GERP RS

4.6

Varity_R

0.18

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