chr4-68932635-G-C

Variant names:

• chr4-68932635-G-C
• rs771807235
• NM_024743.4:c.989C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_024743.4(UGT2A3):​c.989C>G​(p.Pro330Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000871 in 1,606,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: UGT2A3 NM_024743.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.28
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024743.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT2A3	NM_024743.4	MANE Select	c.989C>G	p.Pro330Arg	missense	Exon 3 of 6	NP_079019.3
	UGT2A3	NR_024010.2		n.1130C>G		non_coding_transcript_exon	Exon 4 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT2A3	ENST00000251566.9	TSL:1 MANE Select	c.989C>G	p.Pro330Arg	missense	Exon 3 of 6	ENSP00000251566.4	Q6UWM9
	UGT2A3	ENST00000852414.1		c.1007C>G	p.Pro336Arg	missense	Exon 3 of 6	ENSP00000522473.1
	UGT2A3	ENST00000852415.1		c.865-1393C>G		intron	N/A	ENSP00000522474.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151880 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000162 AC: 4 AN: 246938 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.000308

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000893 AC: 13 AN: 1455090 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 723958

African (AFR) AF: 0.00 AC: 0 AN: 33044

American (AMR) AF: 0.0000457 AC: 2 AN: 43740

Ashkenazi Jewish (ASJ) AF: 0.000117 AC: 3 AN: 25744

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 85444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5226

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1109074

Other (OTH) AF: 0.00 AC: 0 AN: 59936

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151880 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74156

African (AFR) AF: 0.00 AC: 0 AN: 41362

American (AMR) AF: 0.0000657 AC: 1 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.0097	T
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		8.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-8.8	D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.81		Gain of MoRF binding (P = 0.0141)
MVP		0.70
MPC		0.025
ClinPred		0.99	D
GERP RS		2.1
Varity_R		0.42
gMVP		0.41
Mutation Taster		=36/64	disease causing

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

Other links and lift over

dbSNP: rs771807235; hg19: chr4-69798353;