Variant 7-66950954-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_017994.5(TMEM248):c.599A>G(p.Gln200Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000384 in 1,561,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

TMEM248
NM_017994.5 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.63

Variant links:

Genes affected

TMEM248 (HGNC:25476): (transmembrane protein 248) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM248 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30946913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TMEM248	NM_017994.5 linkuse as main transcript	c.599A>G	p.Gln200Arg	missense_variant, splice_region_variant	5/7	ENST00000341567.8
TMEM248	XM_024446819.2 linkuse as main transcript	c.623A>G	p.Gln208Arg	missense_variant, splice_region_variant	5/7
TMEM248	XM_024446820.2 linkuse as main transcript	c.599A>G	p.Gln200Arg	missense_variant, splice_region_variant	5/7
TMEM248	XM_024446821.2 linkuse as main transcript	c.599A>G	p.Gln200Arg	missense_variant, splice_region_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM248	ENST00000341567.8 linkuse as main transcript	c.599A>G	p.Gln200Arg	missense_variant, splice_region_variant	5/7	1	NM_017994.5	P1	Q9NWD8-1
TMEM248	ENST00000433271.6 linkuse as main transcript	c.596+2260A>G		intron_variant, NMD_transcript_variant		1			Q9NWD8-2
TMEM248	ENST00000484751.1 linkuse as main transcript	n.358A>G		splice_region_variant, non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000466

AC:

AN:

214406

Hom.:

AF XY:

0.00000861

AC XY:

AN XY:

116100

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:

0.00000995

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000355

AC:

AN:

1409472

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

696754

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:

0.00000461

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

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:

0.0000147

Gnomad4 OTH

AF:

0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2023

The c.599A>G (p.Q200R) alteration is located in exon 5 (coding exon 4) of the TMEM248 gene. This alteration results from a A to G substitution at nucleotide position 599, causing the glutamine (Q) at amino acid position 200 to be replaced by an arginine (R). 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

0.14

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.031

Eigen

Benign

-0.048

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0047

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.99

MutationAssessor

Benign

2.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.27

REVEL

Benign

0.24

Sift

Benign

0.44

Sift4G

Benign

0.35

Polyphen

0.018

Vest4

0.82

MutPred

0.36

Gain of phosphorylation at T198 (P = 0.1205);

MVP

0.067

MPC

0.37

ClinPred

0.29

GERP RS

5.9

Varity_R

0.12

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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