chr4-5748190-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_153717.3(EVC):​c.982C>T​(p.Leu328Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,614,228 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000064 ( 1 hom. )

Consequence

EVC
NM_153717.3 missense

Scores

7
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 2.18
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.007103622).
BP6
Variant 4-5748190-C-T is Benign according to our data. Variant chr4-5748190-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 349170.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EVCNM_153717.3 linkuse as main transcriptc.982C>T p.Leu328Phe missense_variant 8/21 ENST00000264956.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EVCENST00000264956.11 linkuse as main transcriptc.982C>T p.Leu328Phe missense_variant 8/211 NM_153717.3 P1
EVCENST00000509451.1 linkuse as main transcriptc.982C>T p.Leu328Phe missense_variant 8/121
CRMP1ENST00000506216.5 linkuse as main transcriptn.1770G>A non_coding_transcript_exon_variant 13/135

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152218
Hom.:
0
Cov.:
33
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:
0.00404
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000227
AC:
57
AN:
251488
Hom.:
1
AF XY:
0.000206
AC XY:
28
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00304
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000643
AC:
94
AN:
1461892
Hom.:
1
Cov.:
47
AF XY:
0.0000701
AC XY:
51
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00224
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152336
Hom.:
0
Cov.:
33
AF XY:
0.000201
AC XY:
15
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00405
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000176
Hom.:
0
Bravo
AF:
0.000106
ExAC
AF:
0.000329
AC:
40
Asia WGS
AF:
0.00173
AC:
6
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Ellis-van Creveld syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylMar 08, 2018- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 11, 2020In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in a patient with Jeune asphyxiating thoracic dystrophy in the published literature (McInerney-Leo et al., 2015) who also had a variant in the DNYC2H1 gene and a homozygous variant in the TTC21B gene that was felt to be the cause of the patient's phenotype; This variant is associated with the following publications: (PMID: 28253570, 25492405) -
Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T;.
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.73
T;T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.0071
T;T
MetaSVM
Benign
-0.31
T
MutationAssessor
Uncertain
2.0
M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.44
T
PROVEAN
Uncertain
-2.6
D;D
REVEL
Uncertain
0.41
Sift
Benign
0.11
T;T
Sift4G
Benign
0.18
T;T
Polyphen
1.0
D;.
Vest4
0.22
MVP
0.59
ClinPred
0.14
T
GERP RS
5.0
Varity_R
0.23
gMVP
0.30

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.

Other links and lift over

dbSNP: rs199916502; hg19: chr4-5749917; COSMIC: COSV53832063; COSMIC: COSV53832063; API