chr3-49722998-G-C

Position:

chr3-49722998-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 12/20 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.04

Variant links:

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 links:

GMPPB (HGNC:):

GMPPB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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 id is 260285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49722998-G-C is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GMPPB	NM_021971.4 linkuse as main transcript	c.376C>G	p.His126Asp	missense_variant	4/9	ENST00000308388.7	NP_068806.2	Q9Y5P6-1
GMPPB	NM_013334.4 linkuse as main transcript	c.376C>G	p.His126Asp	missense_variant	4/8		NP_037466.3	Q9Y5P6-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GMPPB	ENST00000308388.7 linkuse as main transcript	c.376C>G	p.His126Asp	missense_variant	4/9	1	NM_021971.4	ENSP00000311130.6		Q9Y5P6-1

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2167

AN:

152190

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0144

AC:

3607

AN:

250542

Hom.:

AF XY:

0.0148

AC XY:

2002

AN XY:

135612

show subpopulations

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 SAS exome

AF:

0.00532

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.:

AF XY:

0.0187

AC XY:

13626

AN XY:

727010

show subpopulations

Gnomad4 AFR exome

AF:

0.00248

Gnomad4 AMR exome

AF:

0.0129

Gnomad4 ASJ exome

AF:

0.0129

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00552

Gnomad4 FIN exome

AF:

0.00925

Gnomad4 NFE exome

AF:

0.0220

Gnomad4 OTH exome

AF:

0.0154

GnomAD4 genome

AF:

0.0142

AC:

2166

AN:

152308

Hom.:

Cov.:

AF XY:

0.0135

AC XY:

1006

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00416

Gnomad4 AMR

AF:

0.0154

Gnomad4 ASJ

AF:

0.0115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00414

Gnomad4 FIN

AF:

0.00819

Gnomad4 NFE

AF:

0.0232

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0197

Hom.:

Bravo

AF:

0.0140

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0205

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0214

AC:

184

ExAC

AF:

0.0153

AC:

1862

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0245

EpiControl

AF:

0.0215

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.40

T;.;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.058

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

.;D;D

MetaRNN

Benign

0.0071

T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

-0.27

N;N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.57

N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.51

T;T;T

Sift4G

Benign

0.46

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.081

MPC

0.75

ClinPred

0.016

GERP RS

4.9

Varity_R

0.22

gMVP

0.47

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over