rs2012025

Positions:

• chr6-1626309-G-A
• chr6-1626309-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001500.4(GMDS):​c.988-1769C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 152,126 control chromosomes in the GnomAD database, including 26,029 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.56 (26029 hom., cov: 34)
  • Exomes 𝑓: 0.17 (0 hom.)
• Consequence: GMDS NM_001500.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.423

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GMDS	NM_001500.4	c.988-1769C>T		intron_variant		ENST00000380815.5
GMDS	NM_001253846.2	c.898-1769C>T		intron_variant
GMDS	XM_011514500.2	c.898-1769C>T		intron_variant
GMDS	XM_017010752.2	c.727-1769C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GMDS	ENST00000380815.5	c.988-1769C>T		intron_variant		1	NM_001500.4	P1
GMDS	ENST00000530927.5	c.898-1769C>T		intron_variant		1
GMDS	ENST00000380805.6	n.1250-1769C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.555 AC: 84412 AN: 152002 Hom.: 25986 Cov.: 34

Gnomad AFR AF: 0.839

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.438

Gnomad EAS AF: 0.531

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.546

GnomAD4 exome AF: 0.167 AC: 1 AN: 6 Hom.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

Gnomad4 AFR exome AF: 0.500

Gnomad4 FIN exome AF: 0.00

GnomAD4 genome AF: 0.556 AC: 84514 AN: 152120 Hom.: 26029 Cov.: 34 AF XY: 0.555 AC XY: 41248 AN XY: 74358

Gnomad4 AFR AF: 0.840

Gnomad4 AMR AF: 0.576

Gnomad4 ASJ AF: 0.438

Gnomad4 EAS AF: 0.531

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.403

Gnomad4 NFE AF: 0.423

Gnomad4 OTH AF: 0.544

Alfa AF: 0.448 Hom.: 20578

Bravo AF: 0.583

Asia WGS AF: 0.488 AC: 1695 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2012025; hg19: chr6-1626544;