4-68931194-T-A

Position:

• chr4-68931194-T-A

Variant summary

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

The NM_024743.4(UGT2A3):​c.1045A>T​(p.Thr349Ser) 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: 1.54

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, 0.898

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT2A3	NM_024743.4	c.1045A>T	p.Thr349Ser	missense_variant	4/6	ENST00000251566.9	NP_079019.3
UGT2A3	XM_011532247.3	c.1063A>T	p.Thr355Ser	missense_variant	4/6		XP_011530549.1
UGT2A3	XM_047416177.1	c.178A>T	p.Thr60Ser	missense_variant	4/6		XP_047272133.1
UGT2A3	NR_024010.2	n.1186A>T		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT2A3	ENST00000251566.9	c.1045A>T	p.Thr349Ser	missense_variant	4/6	1	NM_024743.4	ENSP00000251566	P1
UGT2A3	ENST00000503012.1	c.*221A>T		3_prime_UTR_variant, NMD_transcript_variant	5/7	2		ENSP00000424092

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Mar 20, 2024

The c.1045A>T (p.T349S) alteration is located in exon 4 (coding exon 4) of the UGT2A3 gene. This alteration results from a A to T substitution at nucleotide position 1045, causing the threonine (T) at amino acid position 349 to be replaced by a serine (S). 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	0.60
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.0041	T
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	0.95	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.83		Gain of disorder (P = 0.0715);
MVP		0.44
MPC		0.028
ClinPred		1.0	D
GERP RS		2.0
Varity_R		0.62
gMVP		0.46

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: chr4-69796912;