chr4-39500205-G-A

Position:

chr4-39500205-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_003359.4(UGDH):c.1423C>T(p.Pro475Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000555 in 1,605,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 0 hom. )

Consequence

UGDH
NM_003359.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.357

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_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0057008862).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00054 (82/151798) while in subpopulation NFE AF= 0.000853 (58/67990). AF 95% confidence interval is 0.000678. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGDH	NM_003359.4 linkuse as main transcript	c.1423C>T	p.Pro475Ser	missense_variant	12/12	ENST00000316423.11	NP_003350.1	O60701-1
UGDH	NM_001184700.2 linkuse as main transcript	c.1222C>T	p.Pro408Ser	missense_variant	11/11		NP_001171629.1	O60701-2
UGDH	NM_001184701.2 linkuse as main transcript	c.1132C>T	p.Pro378Ser	missense_variant	11/11		NP_001171630.1	O60701-3
UGDH	XM_005262667.4 linkuse as main transcript	c.1462C>T	p.Pro488Ser	missense_variant	12/12		XP_005262724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
UGDH	ENST00000316423.11 linkuse as main transcript	c.1423C>T	p.Pro475Ser	missense_variant	12/12	1	NM_003359.4	ENSP00000319501.6	O60701-1
UGDH	ENST00000506179.5 linkuse as main transcript	c.1423C>T	p.Pro475Ser	missense_variant	12/12	5		ENSP00000421757.1	O60701-1
UGDH	ENST00000501493.6 linkuse as main transcript	c.1222C>T	p.Pro408Ser	missense_variant	11/11	2		ENSP00000422909.1	O60701-2
UGDH	ENST00000507089.5 linkuse as main transcript	c.1132C>T	p.Pro378Ser	missense_variant	11/11	2		ENSP00000426560.1	O60701-3

Frequencies

GnomAD3 genomes

AF:

0.000541

AC:

AN:

151706

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000291

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000475

AC:

119

AN:

250618

Hom.:

AF XY:

0.000583

AC XY:

AN XY:

135434

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.000465

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000828

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000557

AC:

809

AN:

1453654

Hom.:

Cov.:

AF XY:

0.000621

AC XY:

449

AN XY:

722752

show subpopulations

Gnomad4 AFR exome

AF:

0.0000899

Gnomad4 AMR exome

AF:

0.000382

Gnomad4 ASJ exome

AF:

0.0000386

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000357

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000678

Gnomad4 OTH exome

AF:

0.000451

GnomAD4 genome

AF:

0.000540

AC:

AN:

151798

Hom.:

Cov.:

AF XY:

0.000472

AC XY:

AN XY:

74154

show subpopulations

Gnomad4 AFR

AF:

0.000290

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000853

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000736

Hom.:

Bravo

AF:

0.000635

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000486

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.1423C>T (p.P475S) alteration is located in exon 12 (coding exon 11) of the UGDH gene. This alteration results from a C to T substitution at nucleotide position 1423, causing the proline (P) at amino acid position 475 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

UGDH: PM2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.14

T;.;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.71

.;T;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.0057

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

N;.;N;.

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.16

N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.31

T;T;T;T

Sift4G

Benign

0.25

T;T;T;T

Polyphen

0.0

B;.;B;.

Vest4

0.090

MVP

0.47

MPC

0.27

ClinPred

0.0051

GERP RS

-1.8

Varity_R

0.025

gMVP

0.32

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