3-49721758-G-C

Variant names:

• chr3-49721758-G-C
• rs1553691662
• NM_021971.4:c.1077C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021971.4(GMPPB):​c.1077C>G​(p.Ile359Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: GMPPB NM_021971.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98
• Publications: 0 publications found

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]

RNF123 (HGNC:21148): (ring finger protein 123) The protein encoded by this gene contains a C-terminal RING finger domain, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions, and an N-terminal SPRY domain. This protein displays E3 ubiquitin ligase activity toward the cyclin-dependent kinase inhibitor 1B which is also known as p27 or KIP1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMPPB	NM_021971.4	c.1077C>G	p.Ile359Met	missense_variant	Exon 9 of 9	ENST00000308388.7	NP_068806.2
GMPPB	NM_013334.4	c.1158C>G	p.Ile386Met	missense_variant	Exon 8 of 8		NP_037466.3
RNF123	NM_022064.5	c.*453G>C		downstream_gene_variant		ENST00000327697.11	NP_071347.2
RNF123	NR_135218.2	n.*229G>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPPB	ENST00000308388.7	c.1077C>G	p.Ile359Met	missense_variant	Exon 9 of 9	1	NM_021971.4	ENSP00000311130.6
RNF123	ENST00000327697.11	c.*453G>C		downstream_gene_variant		1	NM_022064.5	ENSP00000328287.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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 Uncertain:1

May 16, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with methionine at codon 359 of the GMPPB protein (p.Ile359Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a GMPPB-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.;D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.51	.;T;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	4.0	H;.;H
PhyloP100		3.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.74
MutPred		0.40		Gain of sheet (P = 0.0344);.;Gain of sheet (P = 0.0344);
MVP		0.86
MPC		1.5
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.75
gMVP		0.91
Mutation Taster		=219/81	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553691662; hg19: chr3-49759191;