rs11243406

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_001077365.2(POMT1):c.1233C>A(p.Asp411Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0497 in 1,614,088 control chromosomes in the GnomAD database, including 2,326 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 129 hom., cov: 33)

Exomes 𝑓: 0.051 ( 2197 hom. )

Consequence

POMT1
NM_001077365.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 2.94

Variant links:

Genes affected

POMT1 (HGNC:9202): (protein O-mannosyltransferase 1) The protein encoded by this gene is an O-mannosyltransferase that requires interaction with the product of the POMT2 gene for enzymatic function. The encoded protein is found in the membrane of the endoplasmic reticulum. Defects in this gene are a cause of Walker-Warburg syndrome (WWS) and limb-girdle muscular dystrophy type 2K (LGMD2K). Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2008]

POMT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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, 4 uncertain in NM_001077365.2

BP4

Computational evidence support a benign effect (MetaRNN=0.008095145).

BP6

Variant 9-131515483-C-A is Benign according to our data. Variant chr9-131515483-C-A is described in ClinVar as [Benign]. Clinvar id is 95455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-131515483-C-A is described in Lovd as [Benign]. Variant chr9-131515483-C-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMT1	NM_001077365.2 linkuse as main transcript	c.1233C>A	p.Asp411Glu	missense_variant	13/20	ENST00000402686.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMT1	ENST00000402686.8 linkuse as main transcript	c.1233C>A	p.Asp411Glu	missense_variant	13/20	1	NM_001077365.2	P1	Q9Y6A1-2

Frequencies

GnomAD3 genomes

AF:

0.0361

AC:

5498

AN:

152222

Hom.:

129

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0217

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0153

Gnomad FIN

AF:

0.0572

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0574

Gnomad OTH

AF:

0.0268

GnomAD3 exomes

AF:

0.0348

AC:

8756

AN:

251496

Hom.:

219

AF XY:

0.0356

AC XY:

4833

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00960

Gnomad AMR exome

AF:

0.0138

Gnomad ASJ exome

AF:

0.0184

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0153

Gnomad FIN exome

AF:

0.0557

Gnomad NFE exome

AF:

0.0533

Gnomad OTH exome

AF:

0.0319

GnomAD4 exome

AF:

0.0511

AC:

74727

AN:

1461748

Hom.:

2197

Cov.:

AF XY:

0.0505

AC XY:

36720

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00762

Gnomad4 AMR exome

AF:

0.0144

Gnomad4 ASJ exome

AF:

0.0184

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0157

Gnomad4 FIN exome

AF:

0.0533

Gnomad4 NFE exome

AF:

0.0598

Gnomad4 OTH exome

AF:

0.0426

GnomAD4 genome

AF:

0.0361

AC:

5496

AN:

152340

Hom.:

129

Cov.:

AF XY:

0.0348

AC XY:

2593

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0104

Gnomad4 AMR

AF:

0.0217

Gnomad4 ASJ

AF:

0.0179

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0153

Gnomad4 FIN

AF:

0.0572

Gnomad4 NFE

AF:

0.0574

Gnomad4 OTH

AF:

0.0265

Alfa

AF:

0.0473

Hom.:

525

Bravo

AF:

0.0316

TwinsUK

AF:

0.0618

AC:

229

ALSPAC

AF:

0.0636

AC:

245

ESP6500AA

AF:

0.0107

AC:

ESP6500EA

AF:

0.0495

AC:

426

ExAC

AF:

0.0342

AC:

4147

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0493

EpiControl

AF:

0.0510

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 23, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2013	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	Genetic Services Laboratory, University of Chicago	Apr 03, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2K

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive limb-girdle muscular dystrophy type 2K;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1;C5436962:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 14, 2017

- -

Walker-Warburg congenital muscular dystrophy;C1836373:Autosomal recessive limb-girdle muscular dystrophy type 2K;C5436962:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.14

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

0.056

Eigen_PC

Benign

-0.063

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

D;D;D;D;.

MetaRNN

Benign

0.0081

T;T;T;T;T

MetaSVM

Benign

-0.34

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.8

D;D;D;D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D

Polyphen

1.0

.;D;.;D;D

Vest4

0.61

MutPred

0.35

.;.;.;Gain of sheet (P = 0.1208);.;

MPC

0.75

ClinPred

0.025

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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