4-39503978-TC-T

Position:

• chr4-39503978-TC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_003359.4(UGDH):​c.1270delG​(p.Asp424fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UGDH NM_003359.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.04

Genes affected

UGDH (HGNC:12525): (UDP-glucose 6-dehydrogenase) The protein encoded by this gene converts UDP-glucose to UDP-glucuronate and thereby participates in the biosynthesis of glycosaminoglycans such as hyaluronan, chondroitin sulfate, and heparan sulfate. These glycosylated compounds are common components of the extracellular matrix and likely play roles in signal transduction, cell migration, and cancer growth and metastasis. The expression of this gene is up-regulated by transforming growth factor beta and down-regulated by hypoxia. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.145 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-39503978-TC-T is Pathogenic according to our data. Variant chr4-39503978-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 3330806.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGDH	NM_003359.4	c.1270delG	p.Asp424fs	frameshift_variant	11/12	ENST00000316423.11	NP_003350.1
UGDH	NM_001184700.2	c.1069delG	p.Asp357fs	frameshift_variant	10/11		NP_001171629.1
UGDH	NM_001184701.2	c.979delG	p.Asp327fs	frameshift_variant	10/11		NP_001171630.1
UGDH	XM_005262667.4	c.1309delG	p.Asp437fs	frameshift_variant	11/12		XP_005262724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGDH	ENST00000316423.11	c.1270delG	p.Asp424fs	frameshift_variant	11/12	1	NM_003359.4	ENSP00000319501.6
UGDH	ENST00000506179.5	c.1270delG	p.Asp424fs	frameshift_variant	11/12	5		ENSP00000421757.1
UGDH	ENST00000501493.6	c.1069delG	p.Asp357fs	frameshift_variant	10/11	2		ENSP00000422909.1
UGDH	ENST00000507089.5	c.979delG	p.Asp327fs	frameshift_variant	10/11	2		ENSP00000426560.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2024

The c.1270delG (p.D424Ifs*10) alteration, located in exon 11 (coding exon 10) of the UGDH gene, consists of a deletion of one nucleotide at position 1270, causing a translational frameshift with a predicted alternate stop codon after 10 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-39505598;