3-49722998-G-C

Variant names:

• chr3-49722998-G-C
• rs34345884
• NM_021971.4:c.376C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021971.4(GMPPB):​c.376C>G​(p.His126Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0184 in 1,613,710 control chromosomes in the GnomAD database, including 327 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (27 hom., cov: 33)
  • Exomes 𝑓: 0.019 (300 hom.)
• Consequence: GMPPB NM_021971.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.04
• Publications: 21 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: Benign. The variant received -18 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.0070964694).
• BP6: Variant 3-49722998-G-C is Benign according to our data. Variant chr3-49722998-G-C is described in ClinVar as Benign. ClinVar VariationId is 260285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0142 (2166/152308) while in subpopulation NFE AF = 0.0232 (1575/68020). AF 95% confidence interval is 0.0222. There are 27 homozygotes in GnomAd4. There are 1006 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

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.376C>G	p.His126Asp	missense	Exon 4 of 9	NP_068806.2
	GMPPB	NM_013334.4		c.376C>G	p.His126Asp	missense	Exon 4 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.376C>G	p.His126Asp	missense	Exon 4 of 9	ENSP00000311130.6
	GMPPB	ENST00000495627.2	TSL:2	c.376C>G	p.His126Asp	missense	Exon 4 of 9	ENSP00000503768.1
	GMPPB	ENST00000308375.10	TSL:2	c.376C>G	p.His126Asp	missense	Exon 4 of 8	ENSP00000309092.6

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2167 AN: 152190 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.00417

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00819

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.0144 AC: 3607 AN: 250542 AF XY: 0.0148

Gnomad AFR exome AF: 0.00309

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00934

Gnomad NFE exome AF: 0.0227

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.0188 AC: 27478 AN: 1461402 Hom.: 300 Cov.: 32 AF XY: 0.0187 AC XY: 13626 AN XY: 727010

African (AFR) AF: 0.00248 AC: 83 AN: 33478

American (AMR) AF: 0.0129 AC: 577 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 336 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00552 AC: 476 AN: 86240

European-Finnish (FIN) AF: 0.00925 AC: 492 AN: 53194

Middle Eastern (MID) AF: 0.0120 AC: 69 AN: 5768

European-Non Finnish (NFE) AF: 0.0220 AC: 24512 AN: 1111790

Other (OTH) AF: 0.0154 AC: 932 AN: 60380

GnomAD4 genome AF: 0.0142 AC: 2166 AN: 152308 Hom.: 27 Cov.: 33 AF XY: 0.0135 AC XY: 1006 AN XY: 74474

African (AFR) AF: 0.00416 AC: 173 AN: 41572

American (AMR) AF: 0.0154 AC: 236 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4828

European-Finnish (FIN) AF: 0.00819 AC: 87 AN: 10618

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0232 AC: 1575 AN: 68020

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.0197 Hom.: 10

Bravo AF: 0.0140

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0214 AC: 184

ExAC AF: 0.0153 AC: 1862

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0245

EpiControl AF: 0.0215

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	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 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.058
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	-0.27	N
PhyloP100		5.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.57	N
REVEL	Uncertain	0.32
Sift	Benign	0.51	T
Sift4G	Benign	0.46	T
Polyphen		0.0010	B
Vest4		0.081
MPC		0.75
ClinPred		0.016	T
GERP RS		4.9
Varity_R		0.22
gMVP		0.47
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34345884; hg19: chr3-49760431;