Genetic Variant TMEM247:p.Arg110Cys (chr2-46480615-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001424184.1(TMEM247):c.328C>T(p.Arg110Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000299 in 1,338,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000030 ( 0 hom. )

Consequence

TMEM247
NM_001424184.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.330

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:

LINC02583 (HGNC:53812): (long intergenic non-protein coding RNA 2583)

LINC02583 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM247	NM_001424184.1 link	c.328C>T	p.Arg110Cys	missense_variant	Exon 2 of 3		NP_001411113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM247	ENST00000434431.2 link	c.328C>T	p.Arg110Cys	missense_variant	Exon 2 of 3	5		ENSP00000388684.1		A6NEH6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

155480

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000299

AC:

AN:

1338868

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

659330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30740

American (AMR)

AF:

0.00

AC:

AN:

33252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23126

East Asian (EAS)

AF:

0.00

AC:

AN:

27786

South Asian (SAS)

AF:

0.00

AC:

AN:

78682

European-Finnish (FIN)

AF:

0.0000228

AC:

AN:

43900

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5394

European-Non Finnish (NFE)

AF:

9.60e-7

AC:

AN:

1041856

Other (OTH)

AF:

0.0000369

AC:

AN:

54132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.328C>T (p.R110C) 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 328, causing the arginine (R) at amino acid position 110 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

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.86

MetaRNN

Uncertain

0.51

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.4

PhyloP100

0.33

PROVEAN

Pathogenic

-7.2

REVEL

Benign

0.19

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

MutPred

0.24

Loss of MoRF binding (P = 0.0078);

MVP

0.27

ClinPred

0.92

GERP RS

2.7

Varity_R

0.090

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

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2-46480615-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over