chr3-49723648-C-G

Variant names:

• chr3-49723648-C-G
• rs142336618
• NM_021971.4:c.79G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM1 PP5_Very_Strong BP4

The NM_021971.4(GMPPB):​c.79G>C​(p.Asp27His) variant causes a missense change. The variant allele was found at a frequency of 0.000951 in 1,582,864 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (1 hom.)
• Consequence: GMPPB NM_021971.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 5.53
• Publications: 22 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_021971.4
• PP5: Variant 3-49723648-C-G is Pathogenic according to our data. Variant chr3-49723648-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 60546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31139874). . 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.79G>C	p.Asp27His	missense	Exon 1 of 9	NP_068806.2	Q9Y5P6-1
	GMPPB	NM_013334.4		c.79G>C	p.Asp27His	missense	Exon 1 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.79G>C	p.Asp27His	missense	Exon 1 of 9	ENSP00000311130.6	Q9Y5P6-1
	GMPPB	ENST00000495627.2	TSL:2	c.79G>C	p.Asp27His	missense	Exon 1 of 9	ENSP00000503768.1	A0A7I2YQI5
	GMPPB	ENST00000308375.10	TSL:2	c.79G>C	p.Asp27His	missense	Exon 1 of 8	ENSP00000309092.6	Q9Y5P6-2

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152266 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000564

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000896

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000704 AC: 157 AN: 222868 AF XY: 0.000742

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00122

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.00112

GnomAD4 exome AF: 0.000997 AC: 1427 AN: 1430598 Hom.: 1 Cov.: 33 AF XY: 0.000919 AC XY: 652 AN XY: 709342

African (AFR) AF: 0.000123 AC: 4 AN: 32626

American (AMR) AF: 0.0000491 AC: 2 AN: 40730

Ashkenazi Jewish (ASJ) AF: 0.0000422 AC: 1 AN: 23704

East Asian (EAS) AF: 0.00 AC: 0 AN: 39486

South Asian (SAS) AF: 0.00 AC: 0 AN: 81494

European-Finnish (FIN) AF: 0.00138 AC: 70 AN: 50906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00121 AC: 1326 AN: 1097036

Other (OTH) AF: 0.000407 AC: 24 AN: 58990

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.000471 AC XY: 35 AN XY: 74384

African (AFR) AF: 0.000217 AC: 9 AN: 41474

American (AMR) AF: 0.000196 AC: 3 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000564 AC: 6 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000896 AC: 61 AN: 68048

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

Alfa AF: 0.000461 Hom.: 0

Bravo AF: 0.000491

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000816 AC: 99

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
3	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2T (3)
3	-	-	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 (3)
2	-	-	GMPPB-related disorder (2)
1	-	-	Acute rhabdomyolysis (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Muscular dystrophy (1)
1	-	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 (1)
1	-	-	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	1.3	L
PhyloP100		5.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.024	D
Sift4G	Benign	0.080	T
Polyphen		0.089	B
Vest4		0.78
MVP		0.93
MPC		1.4
ClinPred		0.57	D
GERP RS		4.8
PromoterAI		-0.059	Neutral
Varity_R		0.81
gMVP		0.62
Mutation Taster		=44/56	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: rs142336618; hg19: chr3-49761081;