chr4-39505342-A-G

Position:

• chr4-39505342-A-G

Variant summary

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

The NM_003359.4(UGDH):​c.1066T>C​(p.Tyr356His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UGDH NM_003359.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.72

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 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	c.1066T>C	p.Tyr356His	missense_variant	9/12	ENST00000316423.11	NP_003350.1
UGDH	NM_001184700.2	c.865T>C	p.Tyr289His	missense_variant	8/11		NP_001171629.1
UGDH	NM_001184701.2	c.775T>C	p.Tyr259His	missense_variant	8/11		NP_001171630.1
UGDH	XM_005262667.4	c.1105T>C	p.Tyr369His	missense_variant	9/12		XP_005262724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGDH	ENST00000316423.11	c.1066T>C	p.Tyr356His	missense_variant	9/12	1	NM_003359.4	ENSP00000319501.6
UGDH	ENST00000506179.5	c.1066T>C	p.Tyr356His	missense_variant	9/12	5		ENSP00000421757.1
UGDH	ENST00000501493.6	c.865T>C	p.Tyr289His	missense_variant	8/11	2		ENSP00000422909.1
UGDH	ENST00000507089.5	c.775T>C	p.Tyr259His	missense_variant	8/11	2		ENSP00000426560.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 84 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Aug 19, 2022

This sequence variant is a single nucleotide substitution (T>C) at coding position 1066 of the UGDH gene that results in a tyrosine to histidine amino acid change at residue 356 of the UGDH protein. This is a novel variant that has not been observed in databases of clinically annotated variants, was not reported in the literature in individuals with UGDH-related disease, and is absent in control population datasets (gnomAD database 0 of ~230,000 alleles). Bioinformatic tools produce mixed predictions as to whether this variant would be tolerated or damaging, and the Tyr356 residue is highly conserved across the vertebrate species examined. This amino acid falls within the UDP binding domain, which is important for the enzymatic activity of UGDH. Functiol studies testing the effect of this variant on protein structure or activity have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this to be a variant of uncertain significance. ACMG Criteria: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;T;.
Eigen	Benign	0.049
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.51	N;.;N;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.35	T;T;T;T
Sift4G	Benign	0.40	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.72
MutPred		0.52		Gain of disorder (P = 0.0301);.;Gain of disorder (P = 0.0301);.;
MVP		0.82
MPC		1.8
ClinPred		0.65	D
GERP RS		6.2
Varity_R		0.58
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-39506962;