rs875989850

Variant names:

• chr3-49722239-C-G
• rs875989850
• NM_021971.4:c.760G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-49722239-C-G
• chr3-49722239-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_021971.4(GMPPB):​c.760G>C​(p.Val254Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V254M) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: GMPPB NM_021971.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67
• Publications: 8 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]

GMPPB Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• myopathy caused by variation in GMPPB

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2T

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
• congenital myasthenic syndrome

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• congenital muscular dystrophy with cerebellar involvement

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myasthenic syndromes with glycosylation defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscle-eye-brain disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-49722239-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMPPB	NM_021971.4	c.760G>C	p.Val254Leu	missense_variant	Exon 7 of 9	ENST00000308388.7	NP_068806.2
GMPPB	NM_013334.4	c.760G>C	p.Val254Leu	missense_variant	Exon 7 of 8		NP_037466.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPPB	ENST00000308388.7	c.760G>C	p.Val254Leu	missense_variant	Exon 7 of 9	1	NM_021971.4	ENSP00000311130.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 43

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74364

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.8	H;H;H
PhyloP100		7.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.063	B;B;B
Vest4		0.91
MutPred		0.41		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.91
MPC		0.75
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.67
gMVP		0.90
Mutation Taster		=17/83	disease causing

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

Other links and lift over

dbSNP: rs875989850; hg19: chr3-49759672;