chr9-131521351-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001077365.2(POMT1):​c.1704G>C​(p.Gln568His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,872 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: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

POMT1
NM_001077365.2 missense

Scores

11
7
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 4.21

Publications

5 publications found
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]
POMT1 Gene-Disease associations (from GenCC):
  • muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Laboratory for Molecular Medicine, Genomics England PanelApp
  • myopathy caused by variation in POMT1
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • autosomal recessive limb-girdle muscular dystrophy type 2K
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • congenital muscular dystrophy with cerebellar involvement
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • congenital muscular dystrophy with intellectual disability
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • congenital muscular dystrophy without intellectual disability
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • muscle-eye-brain disease
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • muscular dystrophy-dystroglycanopathy, type A
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.977
PP5
Variant 9-131521351-G-C is Pathogenic according to our data. Variant chr9-131521351-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3246.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POMT1NM_001077365.2 linkc.1704G>C p.Gln568His missense_variant Exon 18 of 20 ENST00000402686.8 NP_001070833.1 Q9Y6A1-2A0A140VKE0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POMT1ENST00000402686.8 linkc.1704G>C p.Gln568His missense_variant Exon 18 of 20 1 NM_001077365.2 ENSP00000385797.4 Q9Y6A1-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251458
AF XY:
0.00
show subpopulations
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461872
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727236
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53410
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1112002
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Pathogenic:1
May 01, 2006
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

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
Jan 22, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. 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: 3246). This missense change has been observed in individual(s) with clinical features of muscular dystrophy-dystroglycanopathy (PMID: 16575835, 16717220, 18513969). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs119462986, gnomAD 0.0009%). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 590 of the POMT1 protein (p.Gln590His). -

not provided Pathogenic:1
Oct 25, 2013
Eurofins Ntd Llc (ga)
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Uncertain:1
Jul 26, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: POMT1 c.1770G>C (p.Gln590His) results in a non-conservative amino acid change located in the Protein O-mannosyl-transferase, C-terminal four TM domain (IPR032421) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251458 control chromosomes. c.1770G>C has been reported in the literature in compound heterozygous individuals affected with congenital muscular dystrophy with intellectual disability (e.g. vanReeuwijk_2006, Messina_2008). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18513969, 16575835). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.44
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
.;.;.;D;.;D
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.94
D;D;D;D;.;D
M_CAP
Pathogenic
0.52
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.7
.;.;.;M;.;.
PhyloP100
4.2
PrimateAI
Uncertain
0.57
T
PROVEAN
Pathogenic
-4.7
D;D;D;D;D;D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0010
D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
1.0, 1.0
.;D;.;D;D;.
Vest4
0.92
MutPred
0.86
.;.;.;Loss of loop (P = 0.2237);.;.;
MVP
0.96
MPC
0.81
ClinPred
0.99
D
GERP RS
5.1
Varity_R
0.90
gMVP
0.84
Mutation Taster
=1/99
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs119462986; hg19: chr9-134396738; API