rs11547261

Positions:

• chr3-49723044-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021971.4(GMPPB):​c.330C>T​(p.Asp110=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,613,370 control chromosomes in the GnomAD database, including 334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (16 hom., cov: 33)
  • Exomes 𝑓: 0.019 (318 hom.)
• Consequence: GMPPB NM_021971.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.18

Genes affected

GMPPB (HGNC:22932): (GDP-mannose pyrophosphorylase B) This gene is thought to encode a GDP-mannose pyrophosphorylase. The encoded protein catalyzes the conversion of mannose-1-phosphate and GTP to GDP-mannose, a reaction involved in the production of N-linked oligosaccharides. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 3-49723044-G-A is Benign according to our data. Variant chr3-49723044-G-A is described in ClinVar as [Benign]. Clinvar id is 260284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49723044-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.18 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0119 (1812/152280) while in subpopulation NFE AF= 0.02 (1363/68020). AF 95% confidence interval is 0.0192. There are 16 homozygotes in gnomad4. There are 854 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GMPPB	NM_021971.4	c.330C>T	p.Asp110=	synonymous_variant	4/9	ENST00000308388.7
GMPPB	NM_013334.4	c.330C>T	p.Asp110=	synonymous_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GMPPB	ENST00000308388.7	c.330C>T	p.Asp110=	synonymous_variant	4/9	1	NM_021971.4	P1

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1812 AN: 152162 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00352

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0200

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0131 AC: 3294 AN: 251144 Hom.: 32 AF XY: 0.0134 AC XY: 1824 AN XY: 135806

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0107

Gnomad FIN exome AF: 0.00532

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0186 AC: 27210 AN: 1461090 Hom.: 318 Cov.: 31 AF XY: 0.0183 AC XY: 13310 AN XY: 726898

Gnomad4 AFR exome AF: 0.00254

Gnomad4 AMR exome AF: 0.00528

Gnomad4 ASJ exome AF: 0.00635

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.00637

Gnomad4 NFE exome AF: 0.0220

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome AF: 0.0119 AC: 1812 AN: 152280 Hom.: 16 Cov.: 33 AF XY: 0.0115 AC XY: 854 AN XY: 74440

Gnomad4 AFR AF: 0.00351

Gnomad4 AMR AF: 0.00960

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.00452

Gnomad4 NFE AF: 0.0200

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0176 Hom.: 15

Bravo AF: 0.0119

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0184

EpiControl AF: 0.0178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14;C3809221:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14;C4518000:Autosomal recessive limb-girdle muscular dystrophy type 2T Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.34
DANN	Benign	0.86

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

Other links and lift over

dbSNP: rs11547261; hg19: chr3-49760477;