POGLUT1 p.Asp233Glu

Variant names:

• chr3-119486893-T-A
• NM_152305.3:c.699T>A
• POGLUT1 p.Asp233Glu

Your query was ambiguous. Multiple possible variants found:

• chr3-119486893-T-A
• chr3-119486893-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1 PM2 PP3_Moderate

The NM_152305.3(POGLUT1):​c.699T>A​(p.Asp233Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D233Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POGLUT1 NM_152305.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53
• Publications: 0 publications found

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), Ambry Genetics, G2P
• autosomal recessive limb-girdle muscular dystrophy type 2R1

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• Dowling-Degos disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_152305.3 (POGLUT1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152305.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POGLUT1	NM_152305.3	MANE Select	c.699T>A	p.Asp233Glu	missense	Exon 7 of 11	NP_689518.1	Q8NBL1
	POGLUT1	NR_024265.2		n.901T>A		non_coding_transcript_exon	Exon 7 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POGLUT1	ENST00000295588.9	TSL:1 MANE Select	c.699T>A	p.Asp233Glu	missense	Exon 7 of 11	ENSP00000295588.4	Q8NBL1
	POGLUT1	ENST00000937494.1		c.774T>A	p.Asp258Glu	missense	Exon 8 of 12	ENSP00000607553.1
	POGLUT1	ENST00000961895.1		c.693T>A	p.Asp231Glu	missense	Exon 7 of 11	ENSP00000631954.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.35
Sift	Benign	0.099	T
Sift4G	Benign	0.14	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.87
Mutation Taster		=16/84	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-119205740;