rs150367385

chr9-131519447-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001077365.2(POMT1):c.1545C>G(p.Ser515Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,551,390 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: POMT1 NM_001077365.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.25

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015325069).
• BP6: Variant 9-131519447-C-G is Benign according to our data. Variant chr9-131519447-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 162591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-131519447-C-G is described in Lovd as [Pathogenic]. Variant chr9-131519447-C-G is described in Lovd as [Likely_benign]. Variant chr9-131519447-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00116 (1620/1399116) while in subpopulation MID AF= 0.0209 (119/5700). AF 95% confidence interval is 0.0178. There are 2 homozygotes in gnomad4_exome. There are 811 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMT1	NM_001077365.2	c.1545C>G	p.Ser515Arg	missense_variant	16/20	ENST00000402686.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMT1	ENST00000402686.8	c.1545C>G	p.Ser515Arg	missense_variant	16/20	1	NM_001077365.2	P1
	ENST00000415423.1	n.63-2479G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00163 AC: 254 AN: 155618 Hom.: 1 AF XY: 0.00164 AC XY: 134 AN XY: 81892

Gnomad AFR exome AF: 0.000341

Gnomad AMR exome AF: 0.00323

Gnomad ASJ exome AF: 0.00329

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000921

Gnomad FIN exome AF: 0.000536

Gnomad NFE exome AF: 0.00168

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00116 AC: 1620 AN: 1399116 Hom.: 2 Cov.: 32 AF XY: 0.00118 AC XY: 811 AN XY: 690104

Gnomad4 AFR exome AF: 0.000537

Gnomad4 AMR exome AF: 0.00328

Gnomad4 ASJ exome AF: 0.00342

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000795

Gnomad4 FIN exome AF: 0.000678

Gnomad4 NFE exome AF: 0.000990

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74434

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00126

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00157 Hom.: 0

Bravo AF: 0.00140

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000235 AC: 1

ESP6500EA AF: 0.000968 AC: 8

ExAC AF: 0.000687 AC: 54

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 25, 2022	Variant summary: POMT1 c.1611C>G (p.Ser537Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 155618 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 2.3 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. Although listed in the literature, to our knowledge, no penetrant association of c.1611C>G in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a predominant consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 27, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 17, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 18, 2015	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 06, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	POMT1: BS1 -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 26, 2019	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -
Likely benign, no assertion criteria provided	clinical testing	Baylor Genetics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.050
Cadd	Benign	19
Dann	Benign	0.87
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.86	D;D;D;D;.;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.015	T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	0.98	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.18	T;T;T;T;T;T
Sift4G	Benign	0.40	T;T;T;T;T;T
Polyphen		0.0, 0.11	.;B;.;B;B;.
Vest4		0.78
MutPred		0.66		.;.;.;Gain of MoRF binding (P = 0.0199);.;.;
MVP		0.88
MPC		0.28
ClinPred		0.013	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.47

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: rs150367385; hg19: chr9-134394834;