4-68929973-C-A

Variant names:

• chr4-68929973-C-A
• rs369449006
• NM_024743.4:c.1424G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_024743.4(UGT2A3):​c.1424G>T​(p.Arg475Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: UGT2A3 NM_024743.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.88

Genes affected

UGT2A3 (HGNC:28528): (UDP glucuronosyltransferase family 2 member A3) Enables glucuronosyltransferase activity. Involved in cellular glucuronidation. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT2A3	NM_024743.4	c.1424G>T	p.Arg475Leu	missense_variant	Exon 6 of 6	ENST00000251566.9	NP_079019.3
UGT2A3	XM_011532247.3	c.1442G>T	p.Arg481Leu	missense_variant	Exon 6 of 6		XP_011530549.1
UGT2A3	XM_047416177.1	c.557G>T	p.Arg186Leu	missense_variant	Exon 6 of 6		XP_047272133.1
UGT2A3	NR_024010.2	n.1565G>T		non_coding_transcript_exon_variant	Exon 7 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT2A3	ENST00000251566.9	c.1424G>T	p.Arg475Leu	missense_variant	Exon 6 of 6	1	NM_024743.4	ENSP00000251566.4
UGT2A3	ENST00000503012.1	n.*600G>T		non_coding_transcript_exon_variant	Exon 7 of 7	2		ENSP00000424092.1
UGT2A3	ENST00000503012.1	n.*600G>T		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000424092.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250952 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135616

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461442 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 727036

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.35	N
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	4.2	H
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
Polyphen		0.20	B
Vest4		0.52
MutPred		0.85		Loss of methylation at R475 (P = 0.0176);
MVP		0.60
MPC		0.0086
ClinPred		0.99	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		0.48

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: rs369449006; hg19: chr4-69795691;