4-5711382-T-C

Variant names:

• chr4-5711382-T-C
• rs1553857801
• NM_153717.3:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_153717.3(EVC):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EVC NM_153717.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.115
• 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: 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 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 46 pathogenic variants. Next in-frame start position is after 92 codons. Genomic position: 5719347. Lost 0.092 part of the original CDS.
• PS1: Another start lost variant in NM_153717.3 (EVC) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-5711382-T-C is Pathogenic according to our data. Variant chr4-5711382-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2067635.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.2T>C	p.Met1?	start_lost	Exon 1 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.2T>C	p.Met1?	start_lost	Exon 1 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.2T>C	p.Met1?	start_lost	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.2T>C	p.Met1?	start_lost	Exon 1 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 1 of 12	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.98	T
PhyloP100		-0.12
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.16	B
Vest4		0.79
MutPred		1.0		Loss of stability (P = 0.0296)
MVP		0.65
ClinPred		0.21	T
GERP RS		1.1
PromoterAI		-0.083	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.58
Mutation Taster		=13/187	disease causing

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: rs1553857801; hg19: chr4-5713109;