rs890463115

Positions:

• chr9-131518524-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001077365.2(POMT1):​c.1352C>T​(p.Ser451Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S451P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: POMT1 NM_001077365.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.06

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-131518523-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMT1	NM_001077365.2	c.1352C>T	p.Ser451Phe	missense_variant	14/20	ENST00000402686.8	NP_001070833.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMT1	ENST00000402686.8	c.1352C>T	p.Ser451Phe	missense_variant	14/20	1	NM_001077365.2	ENSP00000385797.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250120 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135270

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461226 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726904

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 28, 2016

- -

Walker-Warburg congenital muscular dystrophy;C1836373:Autosomal recessive limb-girdle muscular dystrophy type 2K;C5436962:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POMT1 protein function. ClinVar contains an entry for this variant (Variation ID: 436380). This variant has not been reported in the literature in individuals affected with POMT1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 473 of the POMT1 protein (p.Ser473Phe). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Sep 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;.;.;D;.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D;.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.0	.;.;.;M;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0040	D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;D;D;.
Vest4		0.94
MutPred		0.73		.;.;.;Loss of disorder (P = 0.1001);.;.;
MVP		0.94
MPC		0.94
ClinPred		0.97	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.85
gMVP		0.69

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: rs890463115; hg19: chr9-134393911;