3-119469114-C-T

Variant names:

• chr3-119469114-C-T
• rs769326521
• NM_152305.3:c.85+8C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152305.3(POGLUT1):​c.85+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POGLUT1 NM_152305.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001302
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.262
• 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), 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POGLUT1	NM_152305.3	c.85+8C>T		splice_region_variant, intron_variant	Intron 1 of 10	ENST00000295588.9	NP_689518.1
POGLUT1	NR_024265.2	n.144+8C>T		splice_region_variant, intron_variant	Intron 1 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POGLUT1	ENST00000295588.9	c.85+8C>T		splice_region_variant, intron_variant	Intron 1 of 10	1	NM_152305.3	ENSP00000295588.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439120 Hom.: 0 Cov.: 28 AF XY: 0.00000140 AC XY: 1 AN XY: 715686

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32992

American (AMR) AF: 0.00 AC: 0 AN: 43254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25870

East Asian (EAS) AF: 0.00 AC: 0 AN: 38766

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4832

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102052

Other (OTH) AF: 0.00 AC: 0 AN: 59466

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.87
PhyloP100		0.26
PromoterAI		0.048	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.026
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

Other links and lift over

dbSNP: rs769326521; hg19: chr3-119187961;