5-35965868-A-G

Variant names:

• chr5-35965868-A-G
• rs3756669
• NM_152404.4:c.361T>C

Variant summary

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

The NM_152404.4(UGT3A1):​c.361T>C​(p.Cys121Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,084 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C121Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: UGT3A1 NM_152404.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.52
• Publications: 36 publications found

Genes affected

UGT3A1 (HGNC:26625): (UDP glycosyltransferase family 3 member A1) Enables glucuronosyltransferase activity. Part of UDP-N-acetylglucosamine transferase complex. [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, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT3A1	NM_152404.4	c.361T>C	p.Cys121Arg	missense_variant	Exon 4 of 7	ENST00000274278.8	NP_689617.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT3A1	ENST00000274278.8	c.361T>C	p.Cys121Arg	missense_variant	Exon 4 of 7	1	NM_152404.4	ENSP00000274278.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448084 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 718974

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32794

American (AMR) AF: 0.00 AC: 0 AN: 42398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25556

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.00 AC: 0 AN: 82852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1106600

Other (OTH) AF: 0.00 AC: 0 AN: 59838

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.033899), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T;.;.;.;.
Eigen	Benign	0.13
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.56	T;T;T;.;T
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	4.1	H;.;.;.;.
PhyloP100		1.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-9.0	D;D;D;.;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.72
MutPred		0.72		Gain of disorder (P = 0.0373);Gain of disorder (P = 0.0373);.;.;.;
MVP		0.67
MPC		0.16
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.95
gMVP		0.75
Mutation Taster		=92/8	polymorphism

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: rs3756669; hg19: chr5-35965970;