rs587776619

Variant names:

• chr4-5741746-CT-C
• rs587776619
• NM_153717.3:c.735delT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_153717.3(EVC):​c.735delT​(p.Asp246ThrfsTer27) variant causes a frameshift 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 (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EVC NM_153717.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.0430
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• acrofacial dysostosis, Weyers type

  Inheritance: AD, Unknown, AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Ellis-van Creveld syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-5741746-CT-C is Pathogenic according to our data. Variant chr4-5741746-CT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 5341.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	NM_153717.3	MANE Select	c.735delT	p.Asp246ThrfsTer27	frameshift	Exon 6 of 21	NP_714928.1
	EVC	NM_001306090.2		c.735delT	p.Asp246ThrfsTer27	frameshift	Exon 6 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.735delT	p.Asp246ThrfsTer27	frameshift	Exon 6 of 12	NP_001293021.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	ENST00000264956.11	TSL:1 MANE Select	c.735delT	p.Asp246ThrfsTer27	frameshift	Exon 6 of 21	ENSP00000264956.6
	EVC	ENST00000509451.1	TSL:1	c.735delT	p.Asp246ThrfsTer27	frameshift	Exon 6 of 12	ENSP00000426774.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1421740 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 709246

African (AFR) AF: 0.00 AC: 0 AN: 32806

American (AMR) AF: 0.00 AC: 0 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25770

East Asian (EAS) AF: 0.00 AC: 0 AN: 39356

South Asian (SAS) AF: 0.00 AC: 0 AN: 84782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077072

Other (OTH) AF: 0.00 AC: 0 AN: 58926

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ellis-van Creveld syndrome Pathogenic:1

Mar 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.043
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587776619; hg19: chr4-5743473;