rs750565190

Positions:

• chr4-5741783-T-A
• chr4-5741783-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_153717.3(EVC):​c.770T>A​(p.Leu257Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L257L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.23

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-5741783-T-A is Pathogenic according to our data. Variant chr4-5741783-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191187.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-5741783-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC	NM_153717.3	c.770T>A	p.Leu257Gln	missense_variant	6/21	ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11	c.770T>A	p.Leu257Gln	missense_variant	6/21	1	NM_153717.3	ENSP00000264956	P1
EVC	ENST00000509451.1	c.770T>A	p.Leu257Gln	missense_variant	6/12	1		ENSP00000426774

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1395528 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 697976

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.0059	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.079
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.1	N;D
REVEL	Benign	0.20
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		0.99	D;.
Vest4		0.72
MutPred		0.37		Loss of loop (P = 0.0031);Loss of loop (P = 0.0031);
MVP		0.68
ClinPred		0.92	D
GERP RS		5.1
Varity_R		0.25
gMVP		0.32

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

Other links and lift over

dbSNP: rs750565190; hg19: chr4-5743510;