4-69485256-G-C

Position:

• chr4-69485256-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021139.3(UGT2B4):​c.1262C>G​(p.Ser421Trp) 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: UGT2B4 NM_021139.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

Genes affected

UGT2B4 (HGNC:12553): (UDP glucuronosyltransferase family 2 member B4) Enables glucuronosyltransferase activity. Involved in cellular glucuronidation and estrogen metabolic process. Predicted to be located in endoplasmic reticulum membrane. 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT2B4	NM_021139.3	c.1262C>G	p.Ser421Trp	missense_variant	5/6	ENST00000305107.7	NP_066962.2
UGT2B4	NM_001297616.2	c.854C>G	p.Ser285Trp	missense_variant	6/7		NP_001284545.1
UGT2B4	NM_001297615.2	c.1090+1353C>G		intron_variant			NP_001284544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT2B4	ENST00000305107.7	c.1262C>G	p.Ser421Trp	missense_variant	5/6	1	NM_021139.3	ENSP00000305221	P1
UGT2B4	ENST00000512583.5	c.1090+1353C>G		intron_variant		1		ENSP00000421290
UGT2B4	ENST00000502655.5	n.1139C>G		non_coding_transcript_exon_variant	6/6	5
UGT2B4	ENST00000506580.5	n.872+1353C>G		intron_variant, non_coding_transcript_variant		3

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

Nov 21, 2023

The c.1262C>G (p.S421W) alteration is located in exon 5 (coding exon 5) of the UGT2B4 gene. This alteration results from a C to G substitution at nucleotide position 1262, causing the serine (S) at amino acid position 421 to be replaced by a tryptophan (W). 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	0.57
BayesDel_addAF	Benign	0.0096	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.048	N
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.65		Loss of disorder (P = 0.0253);
MVP		0.44
MPC		0.084
ClinPred		0.87	D
GERP RS		2.0
Varity_R		0.76
gMVP		0.31

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: chr4-70350974;