rs121908426

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_153717.3(EVC):c.919T>C(p.Ser307Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S307C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

EVC
NM_153717.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.0660

Publications

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

EVC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_153717.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.926

PP5

Variant 4-5745321-T-C is Pathogenic according to our data. Variant chr4-5745321-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153717.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EVC	NM_153717.3	MANE Select	c.919T>C	p.Ser307Pro	missense	Exon 7 of 21	NP_714928.1	P57679
EVC	NM_001306090.2		c.919T>C	p.Ser307Pro	missense	Exon 7 of 21	NP_001293019.1
EVC	NM_001306092.2		c.919T>C	p.Ser307Pro	missense	Exon 7 of 12	NP_001293021.1	E9PCN4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EVC	ENST00000264956.11	TSL:1 MANE Select	c.919T>C	p.Ser307Pro	missense	Exon 7 of 21	ENSP00000264956.6	P57679
EVC	ENST00000509451.1	TSL:1	c.919T>C	p.Ser307Pro	missense	Exon 7 of 12	ENSP00000426774.1	E9PCN4
EVC	ENST00000861182.1		c.919T>C	p.Ser307Pro	missense	Exon 7 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000477

AC:

AN:

251472

AF XY:

0.0000515

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1111936

Other (OTH)

AF:

0.0000497

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ellis-van Creveld syndrome (6)

Curry-Hall syndrome (1)

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.84

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.93

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.6

PhyloP100

0.066

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.37

Sift

Benign

0.16

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.70

MutPred

0.67

Gain of glycosylation at S307 (P = 0.0135)

MVP

0.64

ClinPred

0.42

GERP RS

-0.53

Varity_R

0.29

gMVP

0.63

Mutation Taster

=17/83

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over