rs35870680

Variant names:

• chr4-5719322-A-G
• rs35870680
• NM_153717.3:c.249A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_153717.3(EVC):​c.249A>G​(p.Ser83Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,614,116 control chromosomes in the GnomAD database, including 15,096 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1001 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14095 hom.)
• Consequence: EVC NM_153717.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.08
• Publications: 9 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 4-5719322-A-G is Benign according to our data. Variant chr4-5719322-A-G is described in ClinVar as Benign. ClinVar VariationId is 262776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.143 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.249A>G	p.Ser83Ser	synonymous	Exon 2 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.249A>G	p.Ser83Ser	synonymous	Exon 2 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.249A>G	p.Ser83Ser	synonymous	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.249A>G	p.Ser83Ser	synonymous	Exon 2 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.249A>G	p.Ser83Ser	synonymous	Exon 2 of 12	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.249A>G	p.Ser83Ser	synonymous	Exon 2 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15330 AN: 152152 Hom.: 1001 Cov.: 32

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.0842

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.119

GnomAD2 exomes AF: 0.115 AC: 29015 AN: 251472 AF XY: 0.122

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.0633

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.134 AC: 195561 AN: 1461846 Hom.: 14095 Cov.: 34 AF XY: 0.135 AC XY: 98343 AN XY: 727228

African (AFR) AF: 0.0228 AC: 762 AN: 33480

American (AMR) AF: 0.0690 AC: 3087 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 5184 AN: 26136

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39698

South Asian (SAS) AF: 0.129 AC: 11093 AN: 86258

European-Finnish (FIN) AF: 0.134 AC: 7140 AN: 53418

Middle Eastern (MID) AF: 0.170 AC: 978 AN: 5768

European-Non Finnish (NFE) AF: 0.144 AC: 159579 AN: 1111972

Other (OTH) AF: 0.128 AC: 7723 AN: 60394

GnomAD4 genome AF: 0.101 AC: 15327 AN: 152270 Hom.: 1001 Cov.: 32 AF XY: 0.0981 AC XY: 7303 AN XY: 74456

African (AFR) AF: 0.0264 AC: 1098 AN: 41570

American (AMR) AF: 0.0840 AC: 1285 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 657 AN: 3466

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5182

South Asian (SAS) AF: 0.117 AC: 566 AN: 4820

European-Finnish (FIN) AF: 0.132 AC: 1396 AN: 10604

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.145 AC: 9878 AN: 68006

Other (OTH) AF: 0.118 AC: 249 AN: 2112

Alfa AF: 0.129 Hom.: 987

Bravo AF: 0.0939

Asia WGS AF: 0.0540 AC: 186 AN: 3478

EpiCase AF: 0.162

EpiControl AF: 0.163

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Ellis-van Creveld syndrome (3)
-	-	2	not specified (2)
-	-	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
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.40
DANN	Benign	0.31
PhyloP100		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs35870680; hg19: chr4-5721049; COSMIC: COSV53832739;