chr3-49723066-G-A

Position:

• chr3-49723066-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_021971.4(GMPPB):​c.308C>T​(p.Pro103Leu) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P103H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GMPPB NM_021971.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.76

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 3-49723066-G-A is Pathogenic according to our data. Variant chr3-49723066-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225927.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GMPPB	NM_021971.4	c.308C>T	p.Pro103Leu	missense_variant	4/9	ENST00000308388.7
GMPPB	NM_013334.4	c.308C>T	p.Pro103Leu	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GMPPB	ENST00000308388.7	c.308C>T	p.Pro103Leu	missense_variant	4/9	1	NM_021971.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Abnormality of the musculature Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Autosomal recessive limb-girdle muscular dystrophy type 2T Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-9.1	D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.024	D;D;D
Sift4G	Benign	0.11	T;T;T
Polyphen		0.015	B;B;B
Vest4		0.93
MutPred		0.62		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.94
MPC		1.4
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.74
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs875989851; hg19: chr3-49760499;