NM_001077365.2:c.430A>G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_001077365.2(POMT1):c.430A>G(p.Asn144Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

POMT1
NM_001077365.2 missense, splice_region

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.05

Publications

4 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

POMT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001077365.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

PP5

Variant 9-131508913-A-G is Pathogenic according to our data. Variant chr9-131508913-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 39434.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMT1	NM_001077365.2 link	c.430A>G	p.Asn144Asp	missense_variant, splice_region_variant	Exon 6 of 20	ENST00000402686.8	NP_001070833.1	Q9Y6A1-2A0A140VKE0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMT1	ENST00000402686.8 link	c.430A>G	p.Asn144Asp	missense_variant, splice_region_variant	Exon 6 of 20	1	NM_001077365.2	ENSP00000385797.4		Q9Y6A1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1453084

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723622

African (AFR)

AF:

0.00

AC:

AN:

33280

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86070

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104010

Other (OTH)

AF:

0.00

AC:

AN:

60104

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2K

Pathogenic:1

Dec 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

.;.;D;.;D;.;D;D;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D;D;.;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.4

.;M;.;.;M;M;.;.;.

PhyloP100

8.1

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.6

D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.018

D;D;D;D;D;D;T;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D

Polyphen

0.33, 0.71

.;B;.;.;P;B;.;.;.

Vest4

0.96

MutPred

0.81

.;Gain of relative solvent accessibility (P = 0.09);.;.;Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);.;.;.;

MVP

0.95

MPC

0.96

ClinPred

0.99

GERP RS

5.6

Varity_R

0.94

gMVP

0.92

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over