rs202160208

Variant names:

• chr3-49722056-C-T
• rs202160208
• NM_021971.4:c.860G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM5 PP5_Very_Strong BP4

The NM_021971.4(GMPPB):​c.860G>A​(p.Arg287Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000179 in 1,613,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002097271: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID:26133662) - PS3_supporting."" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R287W) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: GMPPB NM_021971.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 U:1
• Conservation: PhyloP100: 4.17
• Publications: 19 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002097271: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 26133662) - PS3_supporting."; SCV003841408: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23768512).; SCV000616733: Published functional studies demonstrate a damaging effect, as C2C12 myoblast cell lines transfected with R287Q showed abnormal subcellular localization of GMPPB resulting in cytoplasmic protein aggregates (PMID: 23768512); SCV000653760: Experimental studies have shown that this missense change affects GMPPB function (PMID: 23768512).; SCV001444987: Functional studies indicate this alteration mildly impairs enzymatic activity of GMPPB compared to other pathogenic alterations (Liu, 2021). In another study, functional analysis demonstrated that the p.R287Q alteration aggregated in the cytoplasm in transfected cells as well as decreased glycosylation of α-dystroglycan in muscle biopsies; however, a later study found that this variant had no effect on protein expression levels (Belaya, 2015; Carss, 2013).; SCV003801067: Functional experiments have shown that the variant has approximately 50% activity compared to the WT protein in an enzymatic activity assay and in vitro, results in the formation of aggregates, affecting the cellular localization of the protein (e.g. Carrs_2013, Liu_2021).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-49722057-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 225925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 3-49722056-C-T is Pathogenic according to our data. Variant chr3-49722056-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 60545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.014596343). . Strength limited to SUPPORTING due to the PP5.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GMPPB	NM_021971.4	MANE Select	c.860G>A	p.Arg287Gln	missense	Exon 8 of 9	NP_068806.2	Q9Y5P6-1
	GMPPB	NM_013334.4		c.860G>A	p.Arg287Gln	missense	Exon 8 of 8	NP_037466.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GMPPB	ENST00000308388.7	TSL:1 MANE Select	c.860G>A	p.Arg287Gln	missense	Exon 8 of 9	ENSP00000311130.6	Q9Y5P6-1
	GMPPB	ENST00000495627.2	TSL:2	c.968G>A	p.Arg323Gln	missense	Exon 8 of 9	ENSP00000503768.1	A0A7I2YQI5
	GMPPB	ENST00000308375.10	TSL:2	c.860G>A	p.Arg287Gln	missense	Exon 8 of 8	ENSP00000309092.6	Q9Y5P6-2

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000288 AC: 72 AN: 249958 AF XY: 0.000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000187

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000178 AC: 260 AN: 1461260 Hom.: 0 Cov.: 44 AF XY: 0.000183 AC XY: 133 AN XY: 726948

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

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00536 AC: 140 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52808

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000755 AC: 84 AN: 1112000

Other (OTH) AF: 0.000397 AC: 24 AN: 60388

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74358

African (AFR) AF: 0.0000483 AC: 2 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68036

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000536 Hom.: 0

Bravo AF: 0.000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	1	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 (4)
4	-	-	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 (4)
4	-	-	not provided (4)
3	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2T (3)
3	-	-	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 (3)
2	-	-	GMPPB-related disorder (2)
1	-	-	Abnormality of the musculature (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.074
FATHMM_MKL	Benign	0.75	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.92	N
PhyloP100		4.2
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.19
Sift	Benign	0.94	T
Sift4G	Benign	0.58	T
Polyphen		0.0030	B
Vest4		0.80
MVP		0.76
MPC		0.64
ClinPred		0.031	T
GERP RS		4.0
Varity_R		0.10
gMVP		0.67
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs202160208; hg19: chr3-49759489;