rs3887873

chr9-131510048-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BA1

The ENST00000372228.9(POMT1):c.751C>T(p.Gln251Ter) 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 ENST00000372228.9 stop_gained
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0490

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]

ACMG classification

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/exons	MANE	UniProt
POMT1	NM_001077365.2	c.699+52C>T		intron_variant		ENST00000402686.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMT1	ENST00000402686.8	c.699+52C>T		intron_variant		1	NM_001077365.2	P1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17877 AN: 152074 Hom.: 1165 Cov.: 33

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

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.: 33 AF XY: 0.118 AC XY: 85891 AN XY: 727210

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.: 33 AF XY: 0.118 AC XY: 8797 AN XY: 74406

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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 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	Eurofins Ntd Llc (ga)	Jul 24, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 28, 2015	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). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 19, 2021	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. -

Autosomal recessive limb-girdle muscular dystrophy type 2K Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.22	T
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	N
MutationTaster	Benign	3.8e-20	P;P;P;P;P;P;P;P
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

Other links and lift over

dbSNP: rs3887873; hg19: chr9-134385435; COSMIC: COSV61225923; COSMIC: COSV61225923;