4-5711380-GA-TT

Position:

• chr4-5711380-GA-TT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_153717.3(EVC):​c.-1_1delinsTT variant causes a start lost, 5 prime UTR 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EVC NM_153717.3 start_lost, 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.74

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-5711380-GA-TT is Pathogenic according to our data. Variant chr4-5711380-GA-TT is described in ClinVar as [Pathogenic]. Clinvar id is 2936900.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC	NM_153717.3	c.-1_1delinsTT		start_lost, 5_prime_UTR_variant	1/21	ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC	ENST00000264956.11	c.-1_1delinsTT		start_lost, 5_prime_UTR_variant	1/21	1	NM_153717.3	P1
EVC	ENST00000509451.1	c.-1_1delinsTT		start_lost, 5_prime_UTR_variant	1/12	1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the EVC protein in which other variant(s) (p.Gly35Asp) have been observed in individuals with EVC-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Disruption of the initiator codon has been observed in individuals with Ellis-van Creveld syndrome (PMID: 19810119, 28854412). It has also been observed to segregate with disease in related individuals. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change affects the initiator methionine of the EVC mRNA. The next in-frame methionine is located at codon 92. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-5713107;