rs6414624

Variant names:

• chr4-5741785-T-C
• rs6414624
• NM_153717.3:c.772T>C

Your query was ambiguous. Multiple possible variants found:

• chr4-5741785-T-C
• chr4-5741785-T-A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_153717.3(EVC):​c.772T>C​(p.Tyr258His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.791 in 1,539,220 control chromosomes in the GnomAD database, including 485,523 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41669 hom., cov: 33)
  • Exomes 𝑓: 0.80 (443854 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.22
• Publications: 40 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: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_153717.3
• BP4: Computational evidence support a benign effect (MetaRNN=6.2664986E-7).
• BP6: Variant 4-5741785-T-C is Benign according to our data. Variant chr4-5741785-T-C is described in ClinVar as Benign. ClinVar VariationId is 198282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.892 is higher than 0.05.

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.772T>C	p.Tyr258His	missense	Exon 6 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.772T>C	p.Tyr258His	missense	Exon 6 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.772T>C	p.Tyr258His	missense	Exon 6 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.772T>C	p.Tyr258His	missense	Exon 6 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.772T>C	p.Tyr258His	missense	Exon 6 of 12	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.772T>C	p.Tyr258His	missense	Exon 6 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.729 AC: 110733 AN: 151944 Hom.: 41650 Cov.: 33

Gnomad AFR AF: 0.531

Gnomad AMI AF: 0.773

Gnomad AMR AF: 0.770

Gnomad ASJ AF: 0.714

Gnomad EAS AF: 0.913

Gnomad SAS AF: 0.820

Gnomad FIN AF: 0.869

Gnomad MID AF: 0.660

Gnomad NFE AF: 0.797

Gnomad OTH AF: 0.739

GnomAD2 exomes AF: 0.797 AC: 199019 AN: 249796 AF XY: 0.800

Gnomad AFR exome AF: 0.527

Gnomad AMR exome AF: 0.806

Gnomad ASJ exome AF: 0.724

Gnomad EAS exome AF: 0.907

Gnomad FIN exome AF: 0.860

Gnomad NFE exome AF: 0.801

Gnomad OTH exome AF: 0.790

GnomAD4 exome AF: 0.797 AC: 1106102 AN: 1387158 Hom.: 443854 Cov.: 25 AF XY: 0.798 AC XY: 553714 AN XY: 694024

African (AFR) AF: 0.514 AC: 16527 AN: 32136

American (AMR) AF: 0.806 AC: 35753 AN: 44386

Ashkenazi Jewish (ASJ) AF: 0.726 AC: 18559 AN: 25552

East Asian (EAS) AF: 0.911 AC: 35690 AN: 39172

South Asian (SAS) AF: 0.824 AC: 69408 AN: 84254

European-Finnish (FIN) AF: 0.861 AC: 45764 AN: 53134

Middle Eastern (MID) AF: 0.709 AC: 3653 AN: 5150

European-Non Finnish (NFE) AF: 0.799 AC: 835595 AN: 1045648

Other (OTH) AF: 0.782 AC: 45153 AN: 57726

GnomAD4 genome AF: 0.729 AC: 110782 AN: 152062 Hom.: 41669 Cov.: 33 AF XY: 0.734 AC XY: 54529 AN XY: 74322

African (AFR) AF: 0.531 AC: 22016 AN: 41482

American (AMR) AF: 0.770 AC: 11755 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.714 AC: 2473 AN: 3466

East Asian (EAS) AF: 0.914 AC: 4738 AN: 5186

South Asian (SAS) AF: 0.821 AC: 3956 AN: 4816

European-Finnish (FIN) AF: 0.869 AC: 9181 AN: 10560

Middle Eastern (MID) AF: 0.645 AC: 187 AN: 290

European-Non Finnish (NFE) AF: 0.798 AC: 54211 AN: 67976

Other (OTH) AF: 0.741 AC: 1563 AN: 2108

Alfa AF: 0.775 Hom.: 130570

Bravo AF: 0.713

TwinsUK AF: 0.814 AC: 3020

ALSPAC AF: 0.800 AC: 3083

ESP6500AA AF: 0.519 AC: 2284

ESP6500EA AF: 0.803 AC: 6902

ExAC AF: 0.794 AC: 96328

Asia WGS AF: 0.834 AC: 2893 AN: 3470

EpiCase AF: 0.794

EpiControl AF: 0.791

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Ellis-van Creveld syndrome (4)
-	-	1	Curry-Hall syndrome (1)
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	6.3e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.033
Sift	Benign	0.43	T
Sift4G	Benign	0.37	T
Polyphen		0.0090	B
Vest4		0.077
ClinPred		0.0039	T
GERP RS		2.7
Varity_R		0.046
gMVP		0.20
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6414624; hg19: chr4-5743512; COSMIC: COSV107299063;