rs41269555

Variant names:

• chr4-5741793-G-A
• rs41269555
• NM_153717.3:c.780G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_153717.3(EVC):​c.780G>A​(p.Lys260Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00862 in 1,519,022 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (86 hom.)
• Consequence: EVC NM_153717.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.525
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 4-5741793-G-A is Benign according to our data. Variant chr4-5741793-G-A is described in ClinVar as Benign. ClinVar VariationId is 198283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.525 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 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.780G>A	p.Lys260Lys	synonymous	Exon 6 of 21	NP_714928.1
	EVC	NM_001306090.2		c.780G>A	p.Lys260Lys	synonymous	Exon 6 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.780G>A	p.Lys260Lys	synonymous	Exon 6 of 12	NP_001293021.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	ENST00000264956.11	TSL:1 MANE Select	c.780G>A	p.Lys260Lys	synonymous	Exon 6 of 21	ENSP00000264956.6
	EVC	ENST00000509451.1	TSL:1	c.780G>A	p.Lys260Lys	synonymous	Exon 6 of 12	ENSP00000426774.1
	EVC	ENST00000861182.1		c.780G>A	p.Lys260Lys	synonymous	Exon 6 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.00655 AC: 996 AN: 152086 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00925

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00777 AC: 1940 AN: 249674 AF XY: 0.00772

Gnomad AFR exome AF: 0.00170

Gnomad AMR exome AF: 0.00178

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.00660

GnomAD4 exome AF: 0.00885 AC: 12102 AN: 1366818 Hom.: 86 Cov.: 23 AF XY: 0.00860 AC XY: 5890 AN XY: 685054

African (AFR) AF: 0.00170 AC: 54 AN: 31820

American (AMR) AF: 0.00180 AC: 80 AN: 44332

Ashkenazi Jewish (ASJ) AF: 0.00263 AC: 67 AN: 25462

East Asian (EAS) AF: 0.00 AC: 0 AN: 39010

South Asian (SAS) AF: 0.0000239 AC: 2 AN: 83748

European-Finnish (FIN) AF: 0.00903 AC: 480 AN: 53144

Middle Eastern (MID) AF: 0.000400 AC: 2 AN: 5006

European-Non Finnish (NFE) AF: 0.0107 AC: 11042 AN: 1027342

Other (OTH) AF: 0.00658 AC: 375 AN: 56954

GnomAD4 genome AF: 0.00654 AC: 995 AN: 152204 Hom.: 4 Cov.: 33 AF XY: 0.00637 AC XY: 474 AN XY: 74418

African (AFR) AF: 0.00173 AC: 72 AN: 41536

American (AMR) AF: 0.00196 AC: 30 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00925 AC: 98 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0114 AC: 777 AN: 68006

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00853 Hom.: 3

Bravo AF: 0.00592

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.00871

EpiControl AF: 0.00961

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Ellis-van Creveld syndrome (2)
-	-	2	not specified (2)
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.6
DANN	Benign	0.59
PhyloP100		0.53
Mutation Taster		=100/0	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: rs41269555; hg19: chr4-5743520;