chr4-5801942-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_153717.3(EVC):c.2305-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 1,612,074 control chromosomes in the GnomAD database, including 432,017 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.72 ( 39628 hom., cov: 33)

Exomes 𝑓: 0.73 ( 392389 hom. )

Consequence

EVC
NM_153717.3 splice_region, intron

Scores

Splicing: ADA: 0.00005523

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.05

Publications

13 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 links:

CRMP1 (HGNC:2365): (collapsin response mediator protein 1) This gene encodes a member of a family of cytosolic phosphoproteins expressed exclusively in the nervous system. The encoded protein is thought to be a part of the semaphorin signal transduction pathway implicated in semaphorin-induced growth cone collapse during neural development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

CRMP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 4-5801942-T-C is Benign according to our data. Variant chr4-5801942-T-C is described in ClinVar as Benign. ClinVar VariationId is 262774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC	NM_153717.3 link	c.2305-8T>C		splice_region_variant, intron_variant	Intron 15 of 20	ENST00000264956.11	NP_714928.1	P57679

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
EVC	ENST00000264956.11 link	c.2305-8T>C	splice_region_variant, intron_variant	Intron 15 of 20	1	NM_153717.3	ENSP00000264956.6	P57679
CRMP1	ENST00000506216.5 link	n.1647+23552A>G	intron_variant	Intron 12 of 12	5
EVC	ENST00000515113.1 link	n.*135T>C	downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.721

AC:

109631

AN:

152034

Hom.:

39592

Cov.:

show subpopulations

Gnomad AFR

AF:

0.708

Gnomad AMI

AF:

0.844

Gnomad AMR

AF:

0.685

Gnomad ASJ

AF:

0.672

Gnomad EAS

AF:

0.551

Gnomad SAS

AF:

0.812

Gnomad FIN

AF:

0.788

Gnomad MID

AF:

0.675

Gnomad NFE

AF:

0.735

Gnomad OTH

AF:

0.704

GnomAD2 exomes

AF:

0.719

AC:

179567

AN:

249798

AF XY:

0.727

show subpopulations

Gnomad AFR exome

AF:

0.716

Gnomad AMR exome

AF:

0.644

Gnomad ASJ exome

AF:

0.685

Gnomad EAS exome

AF:

0.549

Gnomad FIN exome

AF:

0.783

Gnomad NFE exome

AF:

0.733

Gnomad OTH exome

AF:

0.715

GnomAD4 exome

AF:

0.732

AC:

1068320

AN:

1459922

Hom.:

392389

Cov.:

AF XY:

0.734

AC XY:

533351

AN XY:

726242

show subpopulations

African (AFR)

AF:

0.708

AC:

23682

AN:

33438

American (AMR)

AF:

0.650

AC:

28970

AN:

44570

Ashkenazi Jewish (ASJ)

AF:

0.682

AC:

17807

AN:

26114

East Asian (EAS)

AF:

0.537

AC:

21306

AN:

39682

South Asian (SAS)

AF:

0.819

AC:

70540

AN:

86132

European-Finnish (FIN)

AF:

0.776

AC:

41395

AN:

53368

Middle Eastern (MID)

AF:

0.699

AC:

3418

AN:

4890

European-Non Finnish (NFE)

AF:

0.736

AC:

818123

AN:

1111474

Other (OTH)

AF:

0.715

AC:

43079

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

15929

31857

47786

63714

79643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20146

40292

60438

80584

100730

<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:

0.721

AC:

109717

AN:

152152

Hom.:

39628

Cov.:

AF XY:

0.724

AC XY:

53850

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.709

AC:

29404

AN:

41486

American (AMR)

AF:

0.685

AC:

10481

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.672

AC:

2333

AN:

3472

East Asian (EAS)

AF:

0.552

AC:

2844

AN:

5152

South Asian (SAS)

AF:

0.811

AC:

3912

AN:

4824

European-Finnish (FIN)

AF:

0.788

AC:

8358

AN:

10606

Middle Eastern (MID)

AF:

0.668

AC:

195

AN:

292

European-Non Finnish (NFE)

AF:

0.734

AC:

49944

AN:

68000

Other (OTH)

AF:

0.698

AC:

1476

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1634

3267

4901

6534

8168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

840

1680

2520

3360

4200

<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:

0.728

Hom.:

17451

Bravo

AF:

0.708

Asia WGS

AF:

0.678

AC:

2358

AN:

3478

EpiCase

AF:

0.718

EpiControl

AF:

0.722

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Mar 03, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Ellis-van Creveld syndrome

Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Curry-Hall syndrome

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.93

(source)

DANN

Benign

0.61

PhyloP100

-1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000055

dbscSNV1_RF

Benign

0.0020

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over