rs139660235

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001077365.2(POMT1):​c.752C>T​(p.Pro251Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,614,070 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

POMT1
NM_001077365.2 missense

Scores

13
5
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:4

Conservation

PhyloP100: 7.33
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.979
PP5
Variant 9-131510312-C-T is Pathogenic according to our data. Variant chr9-131510312-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95469.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=4}. Variant chr9-131510312-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POMT1NM_001077365.2 linkuse as main transcriptc.752C>T p.Pro251Leu missense_variant 9/20 ENST00000402686.8 NP_001070833.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POMT1ENST00000402686.8 linkuse as main transcriptc.752C>T p.Pro251Leu missense_variant 9/201 NM_001077365.2 ENSP00000385797 P1Q9Y6A1-2

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152196
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251468
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.000123
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:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000239
AC:
35
AN:
1461874
Hom.:
0
Cov.:
35
AF XY:
0.0000193
AC XY:
14
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000243
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152196
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.000145
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000756
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 16, 2024Reported in a study on the pathogencity of variants associated with limb girdle muscular dystrophy; listed as variant seen in the Leiden Open Variation Database, but no additional information was provided (PMID: 25898921); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34532947, 22522420, 25898921) -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 07, 2013- -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityMar 02, 2022- -
Walker-Warburg congenital muscular dystrophy;C1836373:Autosomal recessive limb-girdle muscular dystrophy type 2K;C5436962:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 25, 2023This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 273 of the POMT1 protein (p.Pro273Leu). This variant is present in population databases (rs139660235, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of muscular dystrophy-dystroglycanopathy (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 95469). 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) performed at Invitae indicates that this missense variant is expected to disrupt POMT1 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
POMT1-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesDec 01, 2023The POMT1 c.818C>T variant is predicted to result in the amino acid substitution p.Pro273Leu. This variant was reported in an individual with Walker-Warburg syndrome (reported as c.997C>T (p.Pro273Leu) in Table S1, Willer et al. 2012. PubMed ID: 22522420; Varagur et al. 2022. PubMed ID: 34801143). This variant was also reported in the homozygous state in a fetus with hydrocephalus and additional brain malformations (See #28697; https://assises-genetique.org/sessions-de-posters-affiches/). This variant has also been associated with limb girdle muscular dystrophies, but further information was not available (Table S2, Di Fruscio et al. 2015. PubMed ID: 25898921). Functional studies in patient-derived fibroblast cell lines suggest that this variant might affect normal protein function (reported as POMT1-WWS in Figure 5 and Table S1, Willer et al. 2012. PubMed ID: 22522420). At PreventionGenetics, we have observed the c818C>T variant in the homozygous state in an individual with hydrocephalus and another patient in the compound heterozygous state with a clear pathogenic, loss-of-function variant POMT1 variant (internal data). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/95469/). We interpret this variant as likely pathogenic. -
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 04, 2024- -
Autosomal recessive limb-girdle muscular dystrophy type 2K;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1;C5436962:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.79
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.86
.;.;D;.;D;.;.
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;.;D
M_CAP
Pathogenic
0.39
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.3
.;.;.;.;H;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-5.7
D;D;D;D;D;D;D
REVEL
Pathogenic
0.93
Sift
Uncertain
0.0070
D;D;D;D;D;D;D
Sift4G
Uncertain
0.017
D;D;D;D;D;D;D
Polyphen
1.0, 1.0
.;D;.;.;D;D;.
Vest4
0.89
MVP
0.99
MPC
0.90
ClinPred
0.99
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.81
gMVP
0.87

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs139660235; hg19: chr9-134385699; API