6-1960950-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001500.4(GMDS):c.362C>T(p.Ala121Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,387,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: GMDS NM_001500.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GMDS	NM_001500.4	c.362C>T	p.Ala121Val	missense_variant	5/11	ENST00000380815.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GMDS	ENST00000380815.5	c.362C>T	p.Ala121Val	missense_variant	5/11	1	NM_001500.4	P1
GMDS	ENST00000530927.5	c.272C>T	p.Ala91Val	missense_variant	5/11	1
GMDS	ENST00000530459.1	n.115C>T		non_coding_transcript_exon_variant	2/4	3
GMDS	ENST00000530075.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000101 AC: 14 AN: 1387510 Hom.: 0 Cov.: 31 AF XY: 0.00000585 AC XY: 4 AN XY: 683604

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: 0.0000132

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The c.362C>T (p.A121V) alteration is located in exon 5 (coding exon 5) of the GMDS gene. This alteration results from a C to T substitution at nucleotide position 362, causing the alanine (A) at amino acid position 121 to be replaced by a valine (V). 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	0.75
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Pathogenic	0.89	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.63
MutPred		0.80		.;Loss of catalytic residue at A121 (P = 0.0905);
MVP		0.85
MPC		1.8
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.78

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

Other links and lift over

dbSNP: rs1462367301; hg19: chr6-1961184;