rs756852655

Variant names:

• chr4-5711388-G-C
• rs756852655
• NM_153717.3:c.8G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_153717.3(EVC):​c.8G>C​(p.Arg3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 1,012,094 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R3R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (8 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:4
• Conservation: PhyloP100: 0.655
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.052031577).
• BP6: Variant 4-5711388-G-C is Benign according to our data. Variant chr4-5711388-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193508.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,Unknown,AR gene

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.8G>C	p.Arg3Pro	missense	Exon 1 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.8G>C	p.Arg3Pro	missense	Exon 1 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.8G>C	p.Arg3Pro	missense	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.8G>C	p.Arg3Pro	missense	Exon 1 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.8G>C	p.Arg3Pro	missense	Exon 1 of 12	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.8G>C	p.Arg3Pro	missense	Exon 1 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 280 AN: 148552 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000755

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000939

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00349

Gnomad OTH AF: 0.000978

GnomAD2 exomes AF: 0.00 AC: 0 AN: 392 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00398 AC: 3433 AN: 863436 Hom.: 8 Cov.: 29 AF XY: 0.00389 AC XY: 1569 AN XY: 402872

African (AFR) AF: 0.000306 AC: 5 AN: 16350

American (AMR) AF: 0.00323 AC: 6 AN: 1858

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5786

East Asian (EAS) AF: 0.00 AC: 0 AN: 4968

South Asian (SAS) AF: 0.00 AC: 0 AN: 17500

European-Finnish (FIN) AF: 0.000335 AC: 1 AN: 2984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1760

European-Non Finnish (NFE) AF: 0.00428 AC: 3350 AN: 783258

Other (OTH) AF: 0.00245 AC: 71 AN: 28972

GnomAD4 genome AF: 0.00188 AC: 280 AN: 148658 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 119 AN XY: 72514

African (AFR) AF: 0.000753 AC: 31 AN: 41188

American (AMR) AF: 0.000938 AC: 14 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3428

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00349 AC: 233 AN: 66676

Other (OTH) AF: 0.000967 AC: 2 AN: 2068

Alfa AF: 0.00162 Hom.: 0

Bravo AF: 0.00198

ExAC AF: 0.000631 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	2	-	Ellis-van Creveld syndrome (2)
-	1	1	not specified (2)
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)
-	-	1	EVC-related disorder (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.66
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.12
Sift	Benign	0.35	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.18
MVP		0.65
ClinPred		0.63	D
GERP RS		2.2
PromoterAI		-0.084	Neutral
Varity_R		0.19
gMVP		0.45
Mutation Taster		=93/7	polymorphism

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: rs756852655; hg19: chr4-5713115;