12-90978092-A-T

Position:

• chr12-90978092-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000261172.8(EPYC):​c.336T>A​(p.Asn112Lys) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: EPYC ENST00000261172.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.298

Genes affected

EPYC (HGNC:3053): (epiphycan) Dermatan sulfate proteoglycan 3 is a member of the small leucine-rich repeat proteoglycan family. This gene is composed of seven exons. It regulates fibrillogenesis by interacting with collagen fibrils and other extracellular matrix proteins. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12482241).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPYC	NM_004950.5	c.336T>A	p.Asn112Lys	missense_variant	3/7	ENST00000261172.8	NP_004941.2
EPYC	XM_011538008.2	c.153T>A	p.Asn51Lys	missense_variant	2/6		XP_011536310.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPYC	ENST00000261172.8	c.336T>A	p.Asn112Lys	missense_variant	3/7	1	NM_004950.5	ENSP00000261172	P1
EPYC	ENST00000551767.1	c.336T>A	p.Asn112Lys	missense_variant	3/5	3		ENSP00000448272
EPYC	ENST00000550203.1	n.240T>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

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 21, 2023

The c.336T>A (p.N112K) alteration is located in exon 3 (coding exon 2) of the EPYC gene. This alteration results from a T to A substitution at nucleotide position 336, causing the asparagine (N) at amino acid position 112 to be replaced by a lysine (K). 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	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	10
DANN	Benign	0.93
DEOGEN2	Benign	0.023	T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.90	D
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.051
Sift	Benign	0.14	T;T
Sift4G	Benign	0.72	T;T
Polyphen		0.032	B;.
Vest4		0.26
MutPred		0.48		Gain of methylation at N112 (P = 0.0038);Gain of methylation at N112 (P = 0.0038);
MVP		0.72
MPC		0.016
ClinPred		0.075	T
GERP RS		-1.2
Varity_R		0.077
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1877230772; hg19: chr12-91371869;