4-39503985-C-T

Position:

chr4-39503985-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003359.4(UGDH):c.1264G>A(p.Glu422Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,298 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

UGDH
NM_003359.4 missense, splice_region

Scores

Splicing: ADA: 0.9940

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.77

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGDH	NM_003359.4 linkuse as main transcript	c.1264G>A	p.Glu422Lys	missense_variant, splice_region_variant	11/12	ENST00000316423.11	NP_003350.1	O60701-1
UGDH	NM_001184700.2 linkuse as main transcript	c.1063G>A	p.Glu355Lys	missense_variant, splice_region_variant	10/11		NP_001171629.1	O60701-2
UGDH	NM_001184701.2 linkuse as main transcript	c.973G>A	p.Glu325Lys	missense_variant, splice_region_variant	10/11		NP_001171630.1	O60701-3
UGDH	XM_005262667.4 linkuse as main transcript	c.1303G>A	p.Glu435Lys	missense_variant, splice_region_variant	11/12		XP_005262724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
UGDH	ENST00000316423.11 linkuse as main transcript	c.1264G>A	p.Glu422Lys	missense_variant, splice_region_variant	11/12	1	NM_003359.4	ENSP00000319501.6	O60701-1
UGDH	ENST00000506179.5 linkuse as main transcript	c.1264G>A	p.Glu422Lys	missense_variant, splice_region_variant	11/12	5		ENSP00000421757.1	O60701-1
UGDH	ENST00000501493.6 linkuse as main transcript	c.1063G>A	p.Glu355Lys	missense_variant, splice_region_variant	10/11	2		ENSP00000422909.1	O60701-2
UGDH	ENST00000507089.5 linkuse as main transcript	c.973G>A	p.Glu325Lys	missense_variant, splice_region_variant	10/11	2		ENSP00000426560.1	O60701-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250800

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135596

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461146

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726914

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2024

The c.1264G>A (p.E422K) alteration is located in exon 11 (coding exon 10) of the UGDH gene. This alteration results from a G to A substitution at nucleotide position 1264, causing the glutamic acid (E) at amino acid position 422 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;.;T;.

Eigen

Benign

-0.022

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.52

D;D;D;D

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.1

L;.;L;.

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Uncertain

0.34

Sift

Benign

0.78

T;T;T;T

Sift4G

Benign

0.89

T;T;T;T

Polyphen

0.0010

B;.;B;.

Vest4

0.71

MutPred

0.49

Gain of MoRF binding (P = 0.0377);.;Gain of MoRF binding (P = 0.0377);.;

MVP

0.81

MPC

0.33

ClinPred

0.67

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.38

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.74

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