4-39504478-G-A

Position:

• chr4-39504478-G-A

Variant summary

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

The NM_003359.4(UGDH):​c.1202C>T​(p.Pro401Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: UGDH NM_003359.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.71

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.1202C>T	p.Pro401Leu	missense_variant	10/12	ENST00000316423.11	NP_003350.1
UGDH	NM_001184700.2	c.1001C>T	p.Pro334Leu	missense_variant	9/11		NP_001171629.1
UGDH	NM_001184701.2	c.911C>T	p.Pro304Leu	missense_variant	9/11		NP_001171630.1
UGDH	XM_005262667.4	c.1241C>T	p.Pro414Leu	missense_variant	10/12		XP_005262724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGDH	ENST00000316423.11	c.1202C>T	p.Pro401Leu	missense_variant	10/12	1	NM_003359.4	ENSP00000319501.6
UGDH	ENST00000506179.5	c.1202C>T	p.Pro401Leu	missense_variant	10/12	5		ENSP00000421757.1
UGDH	ENST00000501493.6	c.1001C>T	p.Pro334Leu	missense_variant	9/11	2		ENSP00000422909.1
UGDH	ENST00000507089.5	c.911C>T	p.Pro304Leu	missense_variant	9/11	2		ENSP00000426560.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

UGDH-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 05, 2024

The UGDH c.1202C>T variant is predicted to result in the amino acid substitution p.Pro401Leu. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.66	D;.;D;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	.;D;D;T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.0	L;.;L;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.3	D;D;D;D
REVEL	Uncertain	0.36
Sift	Benign	0.16	T;T;T;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.0070	B;.;B;.
Vest4		0.73
MutPred		0.46		Gain of sheet (P = 0.0149);.;Gain of sheet (P = 0.0149);.;
MVP		0.88
MPC		0.66
ClinPred		0.95	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.88

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: chr4-39506098;