4-39505739-T-C

Position:

• chr4-39505739-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_003359.4(UGDH):​c.916A>G​(p.Met306Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,346 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: UGDH NM_003359.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.67

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.

• PM1: In a helix (size 27) in uniprot entity UGDH_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003359.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-39505739-T-C is Pathogenic according to our data. Variant chr4-39505739-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 810648.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGDH	NM_003359.4	c.916A>G	p.Met306Val	missense_variant	8/12	ENST00000316423.11
UGDH	NM_001184700.2	c.715A>G	p.Met239Val	missense_variant	7/11
UGDH	NM_001184701.2	c.625A>G	p.Met209Val	missense_variant	7/11
UGDH	XM_005262667.4	c.955A>G	p.Met319Val	missense_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGDH	ENST00000316423.11	c.916A>G	p.Met306Val	missense_variant	8/12	1	NM_003359.4	P1
UGDH	ENST00000506179.5	c.916A>G	p.Met306Val	missense_variant	8/12	5		P1
UGDH	ENST00000501493.6	c.715A>G	p.Met239Val	missense_variant	7/11	2
UGDH	ENST00000507089.5	c.625A>G	p.Met209Val	missense_variant	7/11	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454346 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723476

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: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Epileptic encephalopathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Section for Clinical Neurogenetics, University of Tübingen

Oct 01, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.58	D;.;D;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.36	N;.;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Uncertain	0.53
Sift	Benign	0.086	T;T;T;T
Sift4G	Benign	0.59	T;T;T;T
Polyphen		0.17	B;.;B;.
Vest4		0.49
MutPred		0.50		Loss of catalytic residue at M306 (P = 0.1114);.;Loss of catalytic residue at M306 (P = 0.1114);.;
MVP		0.67
MPC		1.5
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.60
gMVP		0.92

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: rs1578265048; hg19: chr4-39507359;