rs3887873

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBA1

The NM_007171.4(POMT1):c.751C>T(p.Gln251*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,613,992 control chromosomes in the GnomAD database, including 12,650 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.12 ( 1165 hom., cov: 33)

Exomes 𝑓: 0.12 ( 11485 hom. )

Consequence

POMT1
NM_007171.4 stop_gained

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.0490

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 -8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 9-131510048-C-T is Benign according to our data. Variant chr9-131510048-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-131510048-C-T is described in Lovd as [Likely_benign]. Variant chr9-131510048-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMT1	NM_001077365.2 link	c.699+52C>T		intron_variant	Intron 8 of 19	ENST00000402686.8	NP_001070833.1	Q9Y6A1-2A0A140VKE0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMT1	ENST00000402686.8 link	c.699+52C>T		intron_variant	Intron 8 of 19	1	NM_001077365.2	ENSP00000385797.4		Q9Y6A1-2

Frequencies

GnomAD3 genomes

AF:

0.118

AC:

17877

AN:

152074

Hom.:

1165

Cov.:

show subpopulations

Gnomad AFR

AF:

0.114

Gnomad AMI

AF:

0.119

Gnomad AMR

AF:

0.100

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0478

Gnomad FIN

AF:

0.150

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.115

GnomAD3 exomes

AF:

0.102

AC:

25489

AN:

251118

Hom.:

1602

AF XY:

0.100

AC XY:

13619

AN XY:

135714

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.0612

Gnomad ASJ exome

AF:

0.115

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0493

Gnomad FIN exome

AF:

0.154

Gnomad NFE exome

AF:

0.132

Gnomad OTH exome

AF:

0.105

GnomAD4 exome

AF:

0.120

AC:

175970

AN:

1461800

Hom.:

11485

Cov.:

AF XY:

0.118

AC XY:

85891

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.108

Gnomad4 AMR exome

AF:

0.0643

Gnomad4 ASJ exome

AF:

0.117

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0530

Gnomad4 FIN exome

AF:

0.156

Gnomad4 NFE exome

AF:

0.132

Gnomad4 OTH exome

AF:

0.111

GnomAD4 genome

AF:

0.118

AC:

17887

AN:

152192

Hom.:

1165

Cov.:

AF XY:

0.118

AC XY:

8797

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.114

Gnomad4 AMR

AF:

0.100

Gnomad4 ASJ

AF:

0.111

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0480

Gnomad4 FIN

AF:

0.150

Gnomad4 NFE

AF:

0.133

Gnomad4 OTH

AF:

0.114

Alfa

AF:

0.119

Hom.:

2223

Bravo

AF:

0.110

TwinsUK

AF:

0.131

AC:

487

ALSPAC

AF:

0.131

AC:

503

ESP6500AA

AF:

0.0897

AC:

395

ESP6500EA

AF:

0.101

AC:

871

ExAC

AF:

0.103

AC:

12565

Asia WGS

AF:

0.0290

AC:

102

AN:

3478

EpiCase

AF:

0.124

EpiControl

AF:

0.122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gln251Trp in exon 8 of POMT1: This variant is not expected to have clinical si gnificance because it has been identified in at least 8.8% (10687/121366) of chr omosomes from multiple diverse populations by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org). -

Jul 24, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 19, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POMT1 c.751C>T (p.Gln251X) results in a premature termination codon. The variant allele was found at a frequency of 0.1 in 251118 control chromosomes in the gnomAD database, including 1602 homozygotes. The observed variant frequency is approximately 140.65 fold of the estimated maximal expected allele frequency for a pathogenic variant in POMT1 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.00072), strongly suggesting that the variant is benign. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Dec 19, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 14, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive limb-girdle muscular dystrophy type 2K

Benign:2

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

0.020

CADD

Benign

0.43

DANN

Benign

0.84

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.011

Vest4

0.34

GERP RS

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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