chr3-49723632-G-C

Variant names:

• chr3-49723632-G-C
• rs397509426
• NM_021971.4:c.95C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_021971.4(GMPPB):​c.95C>G​(p.Pro32Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,432,078 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. P32S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GMPPB NM_021971.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.30
• 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: Pathogenic. The variant received 10 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, 7 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 chr3-49723632-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 60544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMPPB	NM_021971.4	c.95C>G	p.Pro32Arg	missense_variant	Exon 1 of 9	ENST00000308388.7	NP_068806.2
GMPPB	NM_013334.4	c.95C>G	p.Pro32Arg	missense_variant	Exon 1 of 8		NP_037466.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPPB	ENST00000308388.7	c.95C>G	p.Pro32Arg	missense_variant	Exon 1 of 9	1	NM_021971.4	ENSP00000311130.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432078 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 710054

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

African (AFR) AF: 0.00 AC: 0 AN: 32674

American (AMR) AF: 0.00 AC: 0 AN: 41066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23850

East Asian (EAS) AF: 0.00 AC: 0 AN: 39458

South Asian (SAS) AF: 0.00 AC: 0 AN: 82022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097318

Other (OTH) AF: 0.00 AC: 0 AN: 59038

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;H;H
PhyloP100		7.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.3	D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.025	D;D;D
Sift4G	Uncertain	0.017	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.82
MutPred		0.91		Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);
MVP		0.93
MPC		1.5
ClinPred		1.0	D
GERP RS		4.0
PromoterAI		-0.096	Neutral
Varity_R		0.96
gMVP		0.93
Mutation Taster		=7/93	disease causing

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: rs397509426; hg19: chr3-49761065;