chr4-5711341-G-GGCGGCGGGATGCGGCGGGGCGGCAGCCTGAGCGCCCCGGATGGCCC

Variant names:

• chr4-5711341-G-GGCGGCGGGATGCGGCGGGGCGGCAGCCTGAGCGCCCCGGATGGCCC
• NM_153717.3:c.-31_15dupATGCGGCGGGGCGGCAGCCTGAGCGCCCCGGATGGCCCGCGGCGGG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_153717.3(EVC):​c.-31_15dupATGCGGCGGGGCGGCAGCCTGAGCGCCCCGGATGGCCCGCGGCGGG​(p.Ala6fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,256 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000058 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EVC NM_153717.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.0390
• Publications: 0 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: AR, Unknown, AD Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Ellis-van Creveld syndrome

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 230 pathogenic variants in the truncated region.
• PP5: Variant 4-5711341-G-GGCGGCGGGATGCGGCGGGGCGGCAGCCTGAGCGCCCCGGATGGCCC is Pathogenic according to our data. Variant chr4-5711341-G-GGCGGCGGGATGCGGCGGGGCGGCAGCCTGAGCGCCCCGGATGGCCC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3590623.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	NM_153717.3	MANE Select	c.-31_15dupATGCGGCGGGGCGGCAGCCTGAGCGCCCCGGATGGCCCGCGGCGGG	p.Ala6fs	frameshift	Exon 1 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.-31_15dupATGCGGCGGGGCGGCAGCCTGAGCGCCCCGGATGGCCCGCGGCGGG	p.Ala6fs	frameshift	Exon 1 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.-31_15dupATGCGGCGGGGCGGCAGCCTGAGCGCCCCGGATGGCCCGCGGCGGG	p.Ala6fs	frameshift	Exon 1 of 12	NP_001293021.1	E9PCN4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	ENST00000264956.11	TSL:1 MANE Select	c.-31_15dupATGCGGCGGGGCGGCAGCCTGAGCGCCCCGGATGGCCCGCGGCGGG	p.Ala6fs	frameshift	Exon 1 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.-31_15dupATGCGGCGGGGCGGCAGCCTGAGCGCCCCGGATGGCCCGCGGCGGG	p.Ala6fs	frameshift	Exon 1 of 12	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.-31_15dupATGCGGCGGGGCGGCAGCCTGAGCGCCCCGGATGGCCCGCGGCGGG	p.Ala6fs	frameshift	Exon 1 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000584 AC: 5 AN: 856636 Hom.: 0 Cov.: 27 AF XY: 0.0000126 AC XY: 5 AN XY: 398240

African (AFR) AF: 0.00 AC: 0 AN: 16274

American (AMR) AF: 0.00 AC: 0 AN: 1670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5730

East Asian (EAS) AF: 0.00 AC: 0 AN: 4840

South Asian (SAS) AF: 0.000291 AC: 5 AN: 17170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 777852

Other (OTH) AF: 0.00 AC: 0 AN: 28690

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151256 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73954

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67764

Other (OTH) AF: 0.00 AC: 0 AN: 2096

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.039

Splicing

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

Other links and lift over

hg19: chr4-5713068;