rs41269547

Variant names:

• chr4-5719357-A-G
• rs41269547
• NM_153717.3:c.284A>G
• EVC p.Asp95Gly

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_153717.3(EVC):​c.284A>G​(p.Asp95Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00588 in 1,614,184 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D95V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0054 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (39 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:14
• Conservation: PhyloP100: 1.86
• Publications: 6 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044302642).
• BP6: Variant 4-5719357-A-G is Benign according to our data. Variant chr4-5719357-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR,Unknown,AD 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.284A>G	p.Asp95Gly	missense	Exon 2 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.284A>G	p.Asp95Gly	missense	Exon 2 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.284A>G	p.Asp95Gly	missense	Exon 2 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.284A>G	p.Asp95Gly	missense	Exon 2 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.284A>G	p.Asp95Gly	missense	Exon 2 of 12	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.284A>G	p.Asp95Gly	missense	Exon 2 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 826 AN: 152198 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00829

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00808

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00609 AC: 1530 AN: 251320 AF XY: 0.00616

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.0246

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00910

Gnomad NFE exome AF: 0.00818

Gnomad OTH exome AF: 0.00782

GnomAD4 exome AF: 0.00593 AC: 8670 AN: 1461868 Hom.: 39 Cov.: 33 AF XY: 0.00588 AC XY: 4279 AN XY: 727240

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.00291 AC: 130 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 701 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000359 AC: 31 AN: 86258

European-Finnish (FIN) AF: 0.0104 AC: 556 AN: 53416

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.00615 AC: 6839 AN: 1111994

Other (OTH) AF: 0.00599 AC: 362 AN: 60396

GnomAD4 genome AF: 0.00542 AC: 826 AN: 152316 Hom.: 3 Cov.: 32 AF XY: 0.00544 AC XY: 405 AN XY: 74464

African (AFR) AF: 0.000842 AC: 35 AN: 41572

American (AMR) AF: 0.00385 AC: 59 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00829 AC: 88 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00809 AC: 550 AN: 68020

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00734 Hom.: 16

Bravo AF: 0.00454

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00769

EpiControl AF: 0.00818

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	3	Ellis-van Creveld syndrome (3)
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)
-	1	-	Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.9
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.12
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.013	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.27
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41269547; hg19: chr4-5721084;