chr4-39505272-T-A

Position:

• chr4-39505272-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003359.4(UGDH):​c.1136A>T​(p.Asp379Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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: 7.45

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGDH	NM_003359.4	c.1136A>T	p.Asp379Val	missense_variant	9/12	ENST00000316423.11	NP_003350.1
UGDH	NM_001184700.2	c.935A>T	p.Asp312Val	missense_variant	8/11		NP_001171629.1
UGDH	NM_001184701.2	c.845A>T	p.Asp282Val	missense_variant	8/11		NP_001171630.1
UGDH	XM_005262667.4	c.1175A>T	p.Asp392Val	missense_variant	9/12		XP_005262724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGDH	ENST00000316423.11	c.1136A>T	p.Asp379Val	missense_variant	9/12	1	NM_003359.4	ENSP00000319501.6
UGDH	ENST00000506179.5	c.1136A>T	p.Asp379Val	missense_variant	9/12	5		ENSP00000421757.1
UGDH	ENST00000501493.6	c.935A>T	p.Asp312Val	missense_variant	8/11	2		ENSP00000422909.1
UGDH	ENST00000507089.5	c.845A>T	p.Asp282Val	missense_variant	8/11	2		ENSP00000426560.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Neuberg Centre For Genomic Medicine, NCGM

May 20, 2023

The missense c.1136A>T (p.Asp379Val) variant in the UGDH gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is absent in the gnomAD Exomes. The amino acid Aspartic acid at position 379 is changed to a Valine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Probably damaging, SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid Aspartic acid in UGDH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;.;D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.1	M;.;M;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-8.1	D;D;D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		0.57	P;.;P;.
Vest4		0.88
MutPred		0.59		Loss of disorder (P = 0.0563);.;Loss of disorder (P = 0.0563);.;
MVP		0.91
MPC		1.1
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.91
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -15

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: chr4-39506892;