Genetic Variant POGLUT1:p.Leu13Arg (chr3-119469059-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152305.3(POGLUT1):c.38T>G(p.Leu13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

POGLUT1
NM_152305.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.763

Publications

0 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 links:

TMEM39A (HGNC:25600): (transmembrane protein 39A) Involved in negative regulation of autophagosome assembly; negative regulation of autophagosome maturation; and positive regulation of viral genome replication. Located in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM39A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POGLUT1	NM_152305.3 link	c.38T>G	p.Leu13Arg	missense_variant	Exon 1 of 11	ENST00000295588.9	NP_689518.1	Q8NBL1
POGLUT1	NR_024265.2 link	n.97T>G		non_coding_transcript_exon_variant	Exon 1 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POGLUT1	ENST00000295588.9 link	c.38T>G	p.Leu13Arg	missense_variant	Exon 1 of 11	1	NM_152305.3	ENSP00000295588.4		Q8NBL1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000423

AC:

AN:

236388

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:

0.00000964

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä† is likely to be tolerated. This variant has not been reported in the literature in individuals affected with POGLUT1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 13 of the POGLUT1 protein (p.Leu13Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.20

Eigen

Benign

-0.073

Eigen_PC

Benign

0.018

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.62

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.44

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

PhyloP100

0.76

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.2

REVEL

Benign

0.19

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0090

Polyphen

0.54

Vest4

0.49

MutPred

0.61

Gain of MoRF binding (P = 0.002);

MVP

0.47

MPC

0.56

ClinPred

0.66

GERP RS

4.9

PromoterAI

-0.018

Neutral

(source)

Varity_R

0.64

gMVP

0.70

Mutation Taster

=79/21

polymorphism

(source)

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

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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