chr4-39504503-G-A

Position:

• chr4-39504503-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_003359.4(UGDH):​c.1177C>T​(p.Arg393Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,380 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: UGDH NM_003359.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.90

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761
• PP5: Variant 4-39504503-G-A is Pathogenic according to our data. Variant chr4-39504503-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 810645.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGDH	NM_003359.4	c.1177C>T	p.Arg393Trp	missense_variant	10/12	ENST00000316423.11	NP_003350.1
UGDH	NM_001184700.2	c.976C>T	p.Arg326Trp	missense_variant	9/11		NP_001171629.1
UGDH	NM_001184701.2	c.886C>T	p.Arg296Trp	missense_variant	9/11		NP_001171630.1
UGDH	XM_005262667.4	c.1216C>T	p.Arg406Trp	missense_variant	10/12		XP_005262724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGDH	ENST00000316423.11	c.1177C>T	p.Arg393Trp	missense_variant	10/12	1	NM_003359.4	ENSP00000319501.6
UGDH	ENST00000506179.5	c.1177C>T	p.Arg393Trp	missense_variant	10/12	5		ENSP00000421757.1
UGDH	ENST00000501493.6	c.976C>T	p.Arg326Trp	missense_variant	9/11	2		ENSP00000422909.1
UGDH	ENST00000507089.5	c.886C>T	p.Arg296Trp	missense_variant	9/11	2		ENSP00000426560.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250598 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461380 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726954

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Section for Clinical Neurogenetics, University of Tübingen

Oct 01, 2019

- -

Developmental and epileptic encephalopathy, 84 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Feb 23, 2023

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 32001716). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with UGDH related disorder (ClinVar ID: VCV000810645 / PMID: 32001716). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	D;.;D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Uncertain	-0.014	T
MutationAssessor	Benign	1.5	L;.;L;.
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.1	D;D;D;D
REVEL	Uncertain	0.59
Sift	Benign	0.040	D;D;D;D
Sift4G	Uncertain	0.047	D;D;D;D
Polyphen		0.97	D;.;D;.
Vest4		0.60
MutPred		0.56		Gain of sheet (P = 0.0149);.;Gain of sheet (P = 0.0149);.;
MVP		0.94
MPC		0.68
ClinPred		0.94	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.59

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

Other links and lift over

dbSNP: rs113094436; hg19: chr4-39506123;