chr3-49721880-G-T

Variant names:

• chr3-49721880-G-T
• rs780867515
• NM_021971.4:c.955C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_021971.4(GMPPB):​c.955C>A​(p.Arg319Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,674 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. R319H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GMPPB NM_021971.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.87
• 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]

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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_021971.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-49721880-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 569923.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021971.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GMPPB	NM_021971.4	MANE Select	c.955C>A	p.Arg319Ser	missense	Exon 9 of 9	NP_068806.2
	GMPPB	NM_013334.4		c.1036C>A	p.Arg346Ser	missense	Exon 8 of 8	NP_037466.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GMPPB	ENST00000308388.7	TSL:1 MANE Select	c.955C>A	p.Arg319Ser	missense	Exon 9 of 9	ENSP00000311130.6
	GMPPB	ENST00000495627.2	TSL:2	c.1063C>A	p.Arg355Ser	missense	Exon 9 of 9	ENSP00000503768.1
	GMPPB	ENST00000308375.10	TSL:2	c.1036C>A	p.Arg346Ser	missense	Exon 8 of 8	ENSP00000309092.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461674 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727166

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.93
Sift	Benign	0.032	D
Sift4G	Benign	0.080	T
Polyphen		0.43	B
Vest4		0.94
MutPred		0.64		Loss of MoRF binding (P = 0.0224)
MVP		0.91
MPC		1.6
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.72
gMVP		0.89
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: -2

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

Other links and lift over

dbSNP: rs780867515; hg19: chr3-49759313;