Variant rs375431575 details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

PP5

Variant 1-46196047-G-A is Pathogenic according to our data. Variant chr1-46196047-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 558512.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=4, Likely_pathogenic=4}. Variant chr1-46196047-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-46196047-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMGNT1	NM_017739.4 linkuse as main transcript	c.385C>T	p.Arg129Trp	missense_variant	5/22	ENST00000371984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMGNT1	ENST00000371984.8 linkuse as main transcript	c.385C>T	p.Arg129Trp	missense_variant	5/22	1	NM_017739.4	P1	Q8WZA1-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

2

AN:

152110

Hom.:

0

Cov.:

33

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

2

AN:

251224

Hom.:

0

AF XY:

0.0000147

AC XY:

2

AN XY:

135842

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

20

AN:

1461726

Hom.:

0

Cov.:

31

AF XY:

0.0000165

AC XY:

12

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

2

AN:

152110

Hom.:

0

Cov.:

33

AF XY:

0.0000269

AC XY:

2

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000136

Hom.:

0

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000233

AC:

2

ExAC

AF:

0.0000247

AC:

3

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2022	Residue is located within the carbohydrate-binding stem domain and has been shown to modulate O-mannosylation of the alpha-dystroglycan protein; disruptions of this position destabilize the POMGNT1 enzyme, leading to decreased catalytic activity (Kuwabara et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); 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: 34426522, 34324503, 28688748, 27493216, 30961548) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	POMGNT1: PM3:Strong, PM1, PM2, PP3, PS3:Supporting -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 08, 2021	NM_017739.3(POMGNT1):c.385C>T(R129W) is a missense variant classified as likely pathogenic in the context of POMGNT-related disorders. R129W has been observed in cases with relevant disease (PMID: 28688748, 30961548, Kritioti_2019_(no PMID; abstract)). Functional assessments of this variant are not available in the literature. R129W has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, NM_017739.3(POMGNT1):c.385C>T(R129W) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Muscle eye brain disease

Pathogenic:1Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 31, 2020	- -
Likely pathogenic, criteria provided, single submitter	research	Cytogenetics and Genomics Lab, Cyprus Institute Of Neurology and Genetics	Apr 10, 2020	- -

Muscular dystrophy-dystroglycanopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 24, 2023

The p.Arg129Trp variant in POMGNT1 has been reported in at least five individuals with POMGNT1-associated muscular dystrophy-dystroglycanopathy (PMID: 28688748, PMID: 30961548, PMID: 34324503, ClinVar SCV002029242.2), and has been identified in 0.002% (2/113568) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs375431575). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID #558512) and has been interpreted as pathogenic by Invitae and CeGaT Center for Human Genetics Tuebingen, as likely pathogenic by Molecular Genetics (Royal Melbourne Hospital), Cytogenetics and Genomics Lab (Cyprus Institute Of Neurology and Genetics), and Myriad Women's Health, Inc., and as of uncertain significance by Counsyl, Illumina, and Natera, Inc. Of the five affected individuals, two were compound heterozygotes who carried a reported pathogenic or likely pathogenic variant in trans, which increases the likelihood that the p.Arg129Trp variant is pathogenic (PMID: 30961548, PMID: 34324503; ClinvarID: 56582, 984973). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for POMGNT1-associated muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PM3_Strong, PM2_supporting, PP3 (Richards 2015). -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 129 of the POMGNT1 protein (p.Arg129Trp). This variant is present in population databases (rs375431575, gnomAD 0.003%). This missense change has been observed in individual(s) with muscular dystrophy-dystroglycanopathy or congenital muscular dystrophy (PMID: 28688748, 30961548, 34324503; 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: 558512). 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 POMGNT1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Dec 02, 2021

This sequence change in POMGNT1 is predicted to replace arginine with tryptophan at codon 129, p.(Arg129Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and is a critical carbohydrate binding residue in the interleukin-like EMT inducer (ILEI) domain (PMID: 27493216). There is a large physicochemical difference between arginine and tryptophan. The highest population minor allele frequency in gnomAD v2.1 is 0.002% (2/113,568 alleles) in the European (non-Finnish) population, which is consistent with a recessive condition. This variant has been detected in at least four individuals with muscular dystrophy-dystroglycanopathy. Of those individuals, three were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and two of those were confirmed in trans by parental testing (PMID: 28688748, 30961548, 34324503). Further, the variant has been reported to segregate with disease in a single family (PMID: 34324503). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PM1, PM2_Supporting, PP1, PP3. -

Autosomal recessive limb-girdle muscular dystrophy type 2O

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Congenital Muscular Dystrophy, alpha-dystroglycan related

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.32

D

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

31

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;D;.

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.82

D

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.29

D

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Uncertain

0.23

D

MutationAssessor

Uncertain

2.5

.;M;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.91

D

PROVEAN

Pathogenic

-7.7

D;D;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.96

MVP

0.91

MPC

0.91

ClinPred

1.0

D

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.92

gMVP

0.93

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.

rs375431575

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over