Genetic Variant EVC:c.1777-1G>T (chr4-5793607-G-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_153717.3(EVC):c.1777-1G>T variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EVC
NM_153717.3 splice_acceptor, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.01

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	NM_153717.3	MANE Select	c.1777-1G>T		splice_acceptor intron	N/A	NP_714928.1	P57679
	EVC	NM_001306090.2		c.1777-1G>T		splice_acceptor intron	N/A	NP_001293019.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EVC	ENST00000264956.11	TSL:1 MANE Select	c.1777-1G>T	splice_acceptor intron	N/A	ENSP00000264956.6	P57679
EVC	ENST00000861182.1		c.1777-1G>T	splice_acceptor intron	N/A	ENSP00000531241.1
EVC	ENST00000960562.1		c.1639-1G>T	splice_acceptor intron	N/A	ENSP00000630621.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1399386

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690270

African (AFR)

AF:

0.00

AC:

AN:

31646

American (AMR)

AF:

0.00

AC:

AN:

35758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25184

East Asian (EAS)

AF:

0.00

AC:

AN:

35784

South Asian (SAS)

AF:

0.00

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5548

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078898

Other (OTH)

AF:

0.00

AC:

AN:

57994

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Benign

0.72

PhyloP100

5.0

GERP RS

4.9

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.57

Position offset: -4

DS_AL_spliceai

0.98

Position offset: 1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over