Variant 6-2245374-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001500.4(GMDS):c.49G>A(p.Gly17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000974 in 1,550,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

GMDS
NM_001500.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.831

Variant links:

Genes affected

GMDS (HGNC:4369): (GDP-mannose 4,6-dehydratase) GDP-mannose 4,6-dehydratase (GMD; EC 4.2.1.47) catalyzes the conversion of GDP-mannose to GDP-4-keto-6-deoxymannose, the first step in the synthesis of GDP-fucose from GDP-mannose, using NADP+ as a cofactor. The second and third steps of the pathway are catalyzed by a single enzyme, GDP-keto-6-deoxymannose 3,5-epimerase, 4-reductase, designated FX in humans (MIM 137020).[supplied by OMIM, Aug 2009]

GMDS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.005196035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GMDS	NM_001500.4 linkuse as main transcript	c.49G>A	p.Gly17Ser	missense_variant	1/11	ENST00000380815.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GMDS	ENST00000380815.5 linkuse as main transcript	c.49G>A	p.Gly17Ser	missense_variant	1/11	1	NM_001500.4	P1	O60547-1

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000726

AC:

AN:

151438

Hom.:

AF XY:

0.0000599

AC XY:

AN XY:

83450

show subpopulations

Gnomad AFR exome

AF:

0.00134

Gnomad AMR exome

AF:

0.0000380

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000529

AC:

AN:

1398436

Hom.:

Cov.:

AF XY:

0.0000433

AC XY:

AN XY:

692076

show subpopulations

Gnomad4 AFR exome

AF:

0.00202

Gnomad4 AMR exome

AF:

0.0000529

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:

0.00000184

Gnomad4 OTH exome

AF:

0.000120

GnomAD4 genome

AF:

0.000506

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00183

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:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000110

Hom.:

Bravo

AF:

0.000657

ESP6500AA

AF:

0.00118

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000152

AC:

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

Apr 01, 2024

The c.49G>A (p.G17S) alteration is located in exon 1 (coding exon 1) of the GMDS gene. This alteration results from a G to A substitution at nucleotide position 49, causing the glycine (G) at amino acid position 17 to be replaced by a serine (S). 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

0.088

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.56

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.0052

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

MutationTaster

Benign

0.99

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.63

REVEL

Benign

0.047

Sift

Benign

0.14

Sift4G

Benign

0.13

Polyphen

0.0040

Vest4

0.12

MVP

0.37

MPC

0.79

ClinPred

0.052

GERP RS

3.7

Varity_R

0.10

gMVP

0.55

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