Variant chr4-39505748-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_003359.4(UGDH):c.907G>A(p.Val303Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 152,014 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Consequence

UGDH
NM_003359.4 missense, splice_region

Scores

Splicing: ADA: 0.9994

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.57

Variant links:

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]

UGDH links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a helix (size 27) in uniprot entity UGDH_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003359.4

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 4-39505748-C-T is Pathogenic according to our data. Variant chr4-39505748-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 810649.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
UGDH	NM_003359.4 linkuse as main transcript	c.907G>A	p.Val303Ile	missense_variant, splice_region_variant	8/12	ENST00000316423.11
UGDH	NM_001184700.2 linkuse as main transcript	c.706G>A	p.Val236Ile	missense_variant, splice_region_variant	7/11
UGDH	NM_001184701.2 linkuse as main transcript	c.616G>A	p.Val206Ile	missense_variant, splice_region_variant	7/11
UGDH	XM_005262667.4 linkuse as main transcript	c.946G>A	p.Val316Ile	missense_variant, splice_region_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGDH	ENST00000316423.11 linkuse as main transcript	c.907G>A	p.Val303Ile	missense_variant, splice_region_variant	8/12	1	NM_003359.4	P1	O60701-1
UGDH	ENST00000506179.5 linkuse as main transcript	c.907G>A	p.Val303Ile	missense_variant, splice_region_variant	8/12	5		P1	O60701-1
UGDH	ENST00000501493.6 linkuse as main transcript	c.706G>A	p.Val236Ile	missense_variant, splice_region_variant	7/11	2			O60701-2
UGDH	ENST00000507089.5 linkuse as main transcript	c.616G>A	p.Val206Ile	missense_variant, splice_region_variant	7/11	2			O60701-3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000371

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Section for Clinical Neurogenetics, University of Tübingen

Oct 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;.;T;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.97

M_CAP

Pathogenic

0.47

MetaRNN

Uncertain

0.62

D;D;D;D

MetaSVM

Uncertain

0.63

MutationAssessor

Pathogenic

3.6

H;.;H;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.88

N;N;N;N

REVEL

Uncertain

0.63

Sift

Benign

0.058

T;D;T;D

Sift4G

Uncertain

0.041

D;D;D;D

Polyphen

0.96

D;.;D;.

Vest4

0.49

MVP

0.80

MPC

2.1

ClinPred

0.99

GERP RS

5.0

Varity_R

0.43

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.91

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over