4-5711469-C-T

Variant names:

• chr4-5711469-C-T
• rs886044558
• NM_153717.3:c.89C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_153717.3(EVC):​c.89C>T​(p.Pro30Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,066,526 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P30A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (1 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 0.795
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1280435).
• BP6: Variant 4-5711469-C-T is Benign according to our data. Variant chr4-5711469-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 290794.

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.89C>T	p.Pro30Leu	missense	Exon 1 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.89C>T	p.Pro30Leu	missense	Exon 1 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.89C>T	p.Pro30Leu	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.89C>T	p.Pro30Leu	missense	Exon 1 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.89C>T	p.Pro30Leu	missense	Exon 1 of 12	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.89C>T	p.Pro30Leu	missense	Exon 1 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 153 AN: 147864 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000390

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000202

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 4030 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00227 AC: 2088 AN: 918554 Hom.: 1 Cov.: 30 AF XY: 0.00217 AC XY: 940 AN XY: 432490

African (AFR) AF: 0.000453 AC: 8 AN: 17662

American (AMR) AF: 0.00 AC: 0 AN: 4230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7682

East Asian (EAS) AF: 0.00 AC: 0 AN: 9140

South Asian (SAS) AF: 0.0000537 AC: 1 AN: 18628

European-Finnish (FIN) AF: 0.000967 AC: 8 AN: 8270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2032

European-Non Finnish (NFE) AF: 0.00248 AC: 2031 AN: 818778

Other (OTH) AF: 0.00124 AC: 40 AN: 32132

GnomAD4 genome AF: 0.00103 AC: 153 AN: 147972 Hom.: 0 Cov.: 32 AF XY: 0.000915 AC XY: 66 AN XY: 72110

African (AFR) AF: 0.000389 AC: 16 AN: 41118

American (AMR) AF: 0.000201 AC: 3 AN: 14892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3408

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000111 AC: 1 AN: 8990

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

European-Non Finnish (NFE) AF: 0.00200 AC: 133 AN: 66354

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.000963

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.80
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.052
Sift	Benign	0.055	T
Sift4G	Uncertain	0.021	D
Polyphen		0.87	P
Vest4		0.19
MVP		0.58
ClinPred		0.49	T
GERP RS		2.0
PromoterAI		0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.070
gMVP		0.29
Mutation Taster		=77/23	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: rs886044558; hg19: chr4-5713196;