chr4-68930624-G-T

Position:

• chr4-68930624-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024743.4(UGT2A3):​c.1226C>A​(p.Ala409Glu) variant causes a missense change involving the alteration of a non-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: UGT2A3 NM_024743.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.20

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT2A3	NM_024743.4	c.1226C>A	p.Ala409Glu	missense_variant	5/6	ENST00000251566.9	NP_079019.3
UGT2A3	XM_011532247.3	c.1244C>A	p.Ala415Glu	missense_variant	5/6		XP_011530549.1
UGT2A3	XM_047416177.1	c.359C>A	p.Ala120Glu	missense_variant	5/6		XP_047272133.1
UGT2A3	NR_024010.2	n.1367C>A		non_coding_transcript_exon_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT2A3	ENST00000251566.9	c.1226C>A	p.Ala409Glu	missense_variant	5/6	1	NM_024743.4	ENSP00000251566	P1
UGT2A3	ENST00000503012.1	c.*402C>A		3_prime_UTR_variant, NMD_transcript_variant	6/7	2		ENSP00000424092

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2023

The c.1226C>A (p.A409E) alteration is located in exon 5 (coding exon 5) of the UGT2A3 gene. This alteration results from a C to A substitution at nucleotide position 1226, causing the alanine (A) at amino acid position 409 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.70	D
M_CAP	Benign	0.0089	T
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	0.83	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.82		Gain of disorder (P = 0.027);
MVP		0.79
MPC		0.024
ClinPred		0.98	D
GERP RS		2.0
Varity_R		0.72
gMVP		0.57

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: chr4-69796342;