dbSNP rs6414624: EVC:p.Tyr258Asn (chr4-5741785-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1BP4

The NM_153717.3(EVC):c.772T>A(p.Tyr258Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. Y258H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EVC
NM_153717.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.22

Publications

40 publications found

Variant links:

Genes affected

EVC (HGNC:3497): (EvC ciliary complex subunit 1) This gene encodes a protein containing a leucine zipper and a transmembrane domain. This gene has been implicated in both Ellis-van Creveld syndrome (EvC) and Weyers acrodental dysostosis. [provided by RefSeq, Jul 2008]

EVC Gene-Disease associations (from GenCC):

acrofacial dysostosis, Weyers type
Inheritance: AD, Unknown, AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
Ellis-van Creveld syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health

EVC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_153717.3

BP4

Computational evidence support a benign effect (MetaRNN=0.32919645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC	NM_153717.3 link	c.772T>A	p.Tyr258Asn	missense_variant	Exon 6 of 21	ENST00000264956.11	NP_714928.1	P57679

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11 link	c.772T>A	p.Tyr258Asn	missense_variant	Exon 6 of 21	1	NM_153717.3	ENSP00000264956.6		P57679
EVC	ENST00000509451.1 link	c.772T>A	p.Tyr258Asn	missense_variant	Exon 6 of 12	1		ENSP00000426774.1		E9PCN4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152012

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1393796

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

697066

African (AFR)

AF:

0.00

AC:

AN:

32266

American (AMR)

AF:

0.00

AC:

AN:

44436

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25600

East Asian (EAS)

AF:

0.00

AC:

AN:

39190

South Asian (SAS)

AF:

0.00

AC:

AN:

84404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53204

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5180

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1051554

Other (OTH)

AF:

0.00

AC:

AN:

57962

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152012

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74234

African (AFR)

AF:

0.00

AC:

AN:

41396

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2088

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Uncertain

0.45

T;.

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.33

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.3

M;.

PhyloP100

2.2

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.1

D;D

REVEL

Benign

0.16

Sift

Benign

0.20

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.81

P;.

Vest4

0.57

MutPred

0.22

Gain of glycosylation at Y258 (P = 0.0051);Gain of glycosylation at Y258 (P = 0.0051);

MVP

0.65

ClinPred

0.63

GERP RS

2.7

Varity_R

0.13

gMVP

0.29

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over