rs587777297

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_152305.3(POGLUT1):c.835C>T(p.Arg279Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R279Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

POGLUT1
NM_152305.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 7.20

Publications

6 publications found

Variant links:

Genes affected

POGLUT1 (HGNC:22954): (protein O-glucosyltransferase 1) This gene encodes a protein with both O-glucosyltransferase and O-xylosyltransferase activity which localizes to the lumen of the endoplasmic reticulum. This protein has a carboxy-terminal KTEL motif which is predicted to function as an endoplasmic reticulum retention signal. This gene is an essential regulator of Notch signalling and likely plays a role in cell fate and tissue formation during development. It may also play a role in the pathogenesis of leukemia. Mutations in this gene have been associated with the autosomal dominant genodermatosis Dowling-Degos disease 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

POGLUT1 Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Dowling-Degos disease 4
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
autosomal recessive limb-girdle muscular dystrophy type 2R1
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
Dowling-Degos disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

POGLUT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POGLUT1	NM_152305.3 link	c.835C>T	p.Arg279Trp	missense_variant	Exon 9 of 11	ENST00000295588.9	NP_689518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POGLUT1	ENST00000295588.9 link	c.835C>T	p.Arg279Trp	missense_variant	Exon 9 of 11	1	NM_152305.3	ENSP00000295588.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251458

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00000547

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111976

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000472

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dowling-Degos disease 4

Pathogenic:1

Jan 02, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1

Jan 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Experimental studies have shown that this missense change affects POGLUT1 function (PMID: 30414910). 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 POGLUT1 protein function. ClinVar contains an entry for this variant (Variation ID: 126532). This missense change has been observed in individual(s) with Dowling-Degos disease (PMID: 24387993). This variant is present in population databases (rs587777297, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 279 of the POGLUT1 protein (p.Arg279Trp). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.095

MetaRNN

Pathogenic

0.97

MetaSVM

Benign

-0.56

MutationAssessor

Pathogenic

4.0

PhyloP100

7.2

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.7

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MVP

0.75

MPC

1.2

ClinPred

1.0

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.95

Mutation Taster

=5/95

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over