Genetic Variant EPYC:p.Arg194Gln (chr12-90971921-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004950.5(EPYC):c.581G>A(p.Arg194Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,611,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

EPYC
NM_004950.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.959

Variant links:

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]

EPYC links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.073438585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPYC	NM_004950.5 link	c.581G>A	p.Arg194Gln	missense_variant	Exon 5 of 7	ENST00000261172.8	NP_004941.2	Q99645A0A024RBC3
EPYC	XM_011538008.2 link	c.398G>A	p.Arg133Gln	missense_variant	Exon 4 of 6		XP_011536310.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPYC	ENST00000261172.8 link	c.581G>A	p.Arg194Gln	missense_variant	Exon 5 of 7	1	NM_004950.5	ENSP00000261172.3		Q99645
EPYC	ENST00000551767.1 link	c.581G>A	p.Arg194Gln	missense_variant	Exon 5 of 5	3		ENSP00000448272.1		F8VSI4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151896

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000240

AC:

AN:

249546

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000432

AC:

AN:

1459764

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

726238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

AC:

AN:

33452

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44302

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26092

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39552

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

85948

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53336

Gnomad4 NFE exome

AF:

0.0000531

AC:

AN:

1111066

Gnomad4 Remaining exome

AF:

0.0000498

AC:

AN:

60252

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151896

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74172

show subpopulations

Gnomad4 AFR

AF:

0.0000242

AC:

0.000024185

AN:

0.000024185

Gnomad4 AMR

AF:

0.0000656

AC:

0.0000655652

AN:

0.0000655652

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000294

AC:

0.0000294109

AN:

0.0000294109

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 17, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.581G>A (p.R194Q) alteration is located in exon 5 (coding exon 4) of the EPYC gene. This alteration results from a G to A substitution at nucleotide position 581, causing the arginine (R) at amino acid position 194 to be replaced by a glutamine (Q). 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

0.063

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.38

DEOGEN2

Benign

0.0083

T;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.0067

MetaRNN

Benign

0.073

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.21

N;.

PrimateAI

Benign

0.24

PROVEAN

Benign

2.1

N;N

REVEL

Benign

0.099

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0090

B;.

Vest4

0.068

MutPred

0.44

Loss of ubiquitination at K189 (P = 0.0496);Loss of ubiquitination at K189 (P = 0.0496);

MVP

0.64

MPC

0.017

ClinPred

0.067

GERP RS

4.0

Varity_R

0.027

gMVP

0.55

Mutation Taster

=94/6

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over