10-32286818-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001272004.3(EPC1):c.1267T>C(p.Trp423Arg) variant causes a missense change involving the alteration of a 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: EPC1 NM_001272004.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.72

Genes affected

EPC1 (HGNC:19876): (enhancer of polycomb homolog 1) This gene encodes a member of the polycomb group (PcG) family. The encoded protein is a component of the NuA4 histone acetyltransferase complex and can act as both a transcriptional activator and repressor. The encoded protein has been linked to apoptosis, DNA repair, skeletal muscle differentiation, gene silencing, and adult T-cell leukemia/lymphoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, EPC1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPC1	NM_001272004.3	c.1267T>C	p.Trp423Arg	missense_variant	9/14	ENST00000319778.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPC1	ENST00000319778.11	c.1267T>C	p.Trp423Arg	missense_variant	9/14	1	NM_001272004.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Aug 02, 2022

The c.1267T>C (p.W423R) alteration is located in exon 9 (coding exon 9) of the EPC1 gene. This alteration results from a T to C substitution at nucleotide position 1267, causing the tryptophan (W) at amino acid position 423 to be replaced by an arginine (R). 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	0.91
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-10	D;D;D
REVEL	Uncertain	0.55
Sift	Benign	0.030	D;D;D
Sift4G	Uncertain	0.013	D;D;D
Polyphen		0.087	B;D;B
Vest4		0.90
MutPred		0.54		Gain of disorder (P = 0.0099);.;Gain of disorder (P = 0.0099);
MVP		0.62
MPC		1.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.80
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: chr10-32575746;