chr4-39505340-A-C

Position:

• chr4-39505340-A-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_003359.4(UGDH):​c.1068T>G​(p.Tyr356Ter) variant causes a stop gained 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. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UGDH NM_003359.4 stop_gained
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.428

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-39505340-A-C is Pathogenic according to our data. Variant chr4-39505340-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 810647.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGDH	NM_003359.4	c.1068T>G	p.Tyr356Ter	stop_gained	9/12	ENST00000316423.11
UGDH	NM_001184700.2	c.867T>G	p.Tyr289Ter	stop_gained	8/11
UGDH	NM_001184701.2	c.777T>G	p.Tyr259Ter	stop_gained	8/11
UGDH	XM_005262667.4	c.1107T>G	p.Tyr369Ter	stop_gained	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGDH	ENST00000316423.11	c.1068T>G	p.Tyr356Ter	stop_gained	9/12	1	NM_003359.4	P1
UGDH	ENST00000506179.5	c.1068T>G	p.Tyr356Ter	stop_gained	9/12	5		P1
UGDH	ENST00000501493.6	c.867T>G	p.Tyr289Ter	stop_gained	8/11	2
UGDH	ENST00000507089.5	c.777T>G	p.Tyr259Ter	stop_gained	8/11	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Epileptic encephalopathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Section for Clinical Neurogenetics, University of Tübingen

Oct 01, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.96
GERP RS		-0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1260191836; hg19: chr4-39506960;