chr4-39505706-G-A

Position:

chr4-39505706-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_003359.4(UGDH):c.949C>T(p.Arg317Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000808 in 1,608,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R317Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

UGDH
NM_003359.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-39505705-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 592087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
UGDH	NM_003359.4 linkuse as main transcript	c.949C>T	p.Arg317Trp	missense_variant	8/12	ENST00000316423.11
UGDH	NM_001184700.2 linkuse as main transcript	c.748C>T	p.Arg250Trp	missense_variant	7/11
UGDH	NM_001184701.2 linkuse as main transcript	c.658C>T	p.Arg220Trp	missense_variant	7/11
UGDH	XM_005262667.4 linkuse as main transcript	c.988C>T	p.Arg330Trp	missense_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGDH	ENST00000316423.11 linkuse as main transcript	c.949C>T	p.Arg317Trp	missense_variant	8/12	1	NM_003359.4	P1	O60701-1
UGDH	ENST00000506179.5 linkuse as main transcript	c.949C>T	p.Arg317Trp	missense_variant	8/12	5		P1	O60701-1
UGDH	ENST00000501493.6 linkuse as main transcript	c.748C>T	p.Arg250Trp	missense_variant	7/11	2			O60701-2
UGDH	ENST00000507089.5 linkuse as main transcript	c.658C>T	p.Arg220Trp	missense_variant	7/11	2			O60701-3

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151878

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250204

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135286

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000686

AC:

AN:

1456896

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724764

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000721

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151878

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74176

show subpopulations

Gnomad4 AFR

AF:

0.0000726

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;.;D;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.88

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.77

D;D;D;D

MetaSVM

Uncertain

0.28

MutationAssessor

Pathogenic

3.1

M;.;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.1

D;D;D;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.60

MutPred

0.63

Loss of helix (P = 0.0093);.;Loss of helix (P = 0.0093);.;

MVP

0.97

MPC

2.4

ClinPred

0.98

GERP RS

3.0

Varity_R

0.64

gMVP

0.97

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

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