9-131522041-C-A

Position:

• chr9-131522041-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001077365.2(POMT1):​c.1826-6C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,614,002 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (7 hom., cov: 33)
  • Exomes 𝑓: 0.011 (141 hom.)
• Consequence: POMT1 NM_001077365.2 splice_region, intron
• Scores: Splicing: ADA: 0.04315
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0840

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-131522041-C-A is Benign according to our data. Variant chr9-131522041-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 130009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-131522041-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00779 (1186/152328) while in subpopulation NFE AF= 0.0124 (842/68028). AF 95% confidence interval is 0.0117. There are 7 homozygotes in gnomad4. There are 556 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMT1	NM_001077365.2	c.1826-6C>A		splice_region_variant, intron_variant		ENST00000402686.8	NP_001070833.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMT1	ENST00000402686.8	c.1826-6C>A		splice_region_variant, intron_variant		1	NM_001077365.2	ENSP00000385797.4

Frequencies

GnomAD3 genomes AF: 0.00779 AC: 1186 AN: 152210 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00669

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00696 AC: 1749 AN: 251326 Hom.: 11 AF XY: 0.00656 AC XY: 892 AN XY: 135884

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00677

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.00798

GnomAD4 exome AF: 0.0112 AC: 16442 AN: 1461674 Hom.: 141 Cov.: 31 AF XY: 0.0107 AC XY: 7806 AN XY: 727168

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.00402

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00650

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.00954

GnomAD4 genome AF: 0.00779 AC: 1186 AN: 152328 Hom.: 7 Cov.: 33 AF XY: 0.00746 AC XY: 556 AN XY: 74490

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00669

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00991 Hom.: 5

Bravo AF: 0.00773

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0111

EpiControl AF: 0.00931

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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.1892-6C>A in intron 18 of POMT1: This variant is not expected to have clinical significance because it has been identified in 1.5% (125/8600) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs140258585). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 30, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	POMT1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 16, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2K Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.0
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.043
dbscSNV1_RF	Benign	0.20
SpliceAI score (max)		0.090		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: rs140258585; hg19: chr9-134397428;