chr9-131519447-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001077365.2(POMT1):ā€‹c.1545C>Gā€‹(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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0012 ( 0 hom., cov: 32)
Exomes š‘“: 0.0012 ( 2 hom. )

Consequence

POMT1
NM_001077365.2 missense

Scores

4
15

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.25
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POMT1NM_001077365.2 linkc.1545C>G p.Ser515Arg missense_variant Exon 16 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.1545C>G p.Ser515Arg missense_variant Exon 16 of 20 1 NM_001077365.2 ENSP00000385797.4 Q9Y6A1-2

Frequencies

GnomAD3 genomes
AF:
0.00120
AC:
183
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not specified Benign:6
Sep 17, 2015
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 30, 2017
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Feb 08, 2024
Athena Diagnostics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 18, 2015
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 25, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:2
May 06, 2016
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

POMT1: BS1 -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 Benign:2
Mar 26, 2019
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

-
Baylor Genetics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2K Benign:1
May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
DEOGEN2
Benign
0.30
.;.;.;T;.;T
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
MutationAssessor
Benign
1.6
.;.;.;L;.;.
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

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

Other links and lift over

dbSNP: rs150367385; hg19: chr9-134394834; API