rs4740165

Positions:

• chr9-131522237-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001077365.2(POMT1):​c.2003+13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.922 in 1,612,548 control chromosomes in the GnomAD database, including 689,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (55947 hom., cov: 33)
  • Exomes 𝑓: 0.93 (633308 hom.)
• Consequence: POMT1 NM_001077365.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.60

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-131522237-C-T is Benign according to our data. Variant chr9-131522237-C-T is described in ClinVar as [Benign]. Clinvar id is 95460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-131522237-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.939 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMT1	NM_001077365.2	c.2003+13C>T		intron_variant		ENST00000402686.8	NP_001070833.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMT1	ENST00000402686.8	c.2003+13C>T		intron_variant		1	NM_001077365.2	ENSP00000385797	P1
	ENST00000415423.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.848 AC: 128966 AN: 152100 Hom.: 55928 Cov.: 33

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.897

Gnomad AMR AF: 0.846

Gnomad ASJ AF: 0.923

Gnomad EAS AF: 0.917

Gnomad SAS AF: 0.962

Gnomad FIN AF: 0.934

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.938

Gnomad OTH AF: 0.864

GnomAD3 exomes AF: 0.902 AC: 225334 AN: 249940 Hom.: 102434 AF XY: 0.912 AC XY: 123463 AN XY: 135376

Gnomad AFR exome AF: 0.636

Gnomad AMR exome AF: 0.829

Gnomad ASJ exome AF: 0.925

Gnomad EAS exome AF: 0.914

Gnomad SAS exome AF: 0.961

Gnomad FIN exome AF: 0.932

Gnomad NFE exome AF: 0.935

Gnomad OTH exome AF: 0.913

GnomAD4 exome AF: 0.930 AC: 1357755 AN: 1460330 Hom.: 633308 Cov.: 76 AF XY: 0.932 AC XY: 676988 AN XY: 726600

Gnomad4 AFR exome AF: 0.633

Gnomad4 AMR exome AF: 0.830

Gnomad4 ASJ exome AF: 0.925

Gnomad4 EAS exome AF: 0.916

Gnomad4 SAS exome AF: 0.962

Gnomad4 FIN exome AF: 0.931

Gnomad4 NFE exome AF: 0.942

Gnomad4 OTH exome AF: 0.909

GnomAD4 genome AF: 0.848 AC: 129020 AN: 152218 Hom.: 55947 Cov.: 33 AF XY: 0.850 AC XY: 63258 AN XY: 74436

Gnomad4 AFR AF: 0.647

Gnomad4 AMR AF: 0.846

Gnomad4 ASJ AF: 0.923

Gnomad4 EAS AF: 0.917

Gnomad4 SAS AF: 0.962

Gnomad4 FIN AF: 0.934

Gnomad4 NFE AF: 0.938

Gnomad4 OTH AF: 0.865

Alfa AF: 0.915 Hom.: 59029

Bravo AF: 0.829

Asia WGS AF: 0.890 AC: 3092 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Eurofins Ntd Llc (ga)	Apr 23, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.2069+13C>T in intron 19 of POMT1: This variant is not expected to have clinica l significance because it is not located within the conserved splice consensus s equence. It has been identified in 35.2% (1549/4406) of African American chromos omes from a broad population by the NHLBI Exome Sequencing Project (http://evs.g s.washington.edu/EVS; dbSNP rs4740165). -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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_noAF	Benign	-0.89
CADD	Benign	1.0
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs4740165; hg19: chr9-134397624;