chr4-5748148-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_153717.3(EVC):ā€‹c.940A>Gā€‹(p.Met314Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000031 in 1,614,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict 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 Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 34)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

EVC
NM_153717.3 missense, splice_region

Scores

3
16
Splicing: ADA: 0.00002635
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.77
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 Uncertain_significance. Variant got 2 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, 4 uncertain in NM_153717.3
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.26324195).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EVCNM_153717.3 linkuse as main transcriptc.940A>G p.Met314Val missense_variant, splice_region_variant 8/21 ENST00000264956.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EVCENST00000264956.11 linkuse as main transcriptc.940A>G p.Met314Val missense_variant, splice_region_variant 8/211 NM_153717.3 P1
EVCENST00000509451.1 linkuse as main transcriptc.940A>G p.Met314Val missense_variant, splice_region_variant 8/121
CRMP1ENST00000506216.5 linkuse as main transcriptn.1812T>C non_coding_transcript_exon_variant 13/135

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152194
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000241
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
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251480
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461880
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152312
Hom.:
0
Cov.:
34
AF XY:
0.0000134
AC XY:
1
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeNov 08, 2021In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with EVC-related conditions. This variant is present in population databases (rs557010916, gnomAD 0.007%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 314 of the EVC protein (p.Met314Val). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
19
DANN
Benign
0.89
DEOGEN2
Benign
0.36
T;.
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.19
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.26
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.5
M;.
MutationTaster
Benign
0.92
D;D;D
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-2.2
N;D
REVEL
Benign
0.17
Sift
Benign
0.14
T;T
Sift4G
Benign
0.23
T;T
Polyphen
0.21
B;.
Vest4
0.60
MutPred
0.55
Loss of disorder (P = 0.1607);Loss of disorder (P = 0.1607);
MVP
0.30
ClinPred
0.17
T
GERP RS
2.4
Varity_R
0.11
gMVP
0.38

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000026
dbscSNV1_RF
Benign
0.0040
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: rs557010916; hg19: chr4-5749875; API