NM_153717.3:c.14G>T

Variant names:

• chr4-5711394-G-T
• rs939779373
• NM_153717.3:c.14G>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.14G>T​(p.Gly5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,014,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -3.49
• Publications: 0 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=0.07313606).
• BP6: Variant 4-5711394-G-T is Benign according to our data. Variant chr4-5711394-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2928212.

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.14G>T	p.Gly5Val	missense	Exon 1 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.14G>T	p.Gly5Val	missense	Exon 1 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.14G>T	p.Gly5Val	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.14G>T	p.Gly5Val	missense	Exon 1 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.14G>T	p.Gly5Val	missense	Exon 1 of 12	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.14G>T	p.Gly5Val	missense	Exon 1 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.0000674 AC: 10 AN: 148396 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000671

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000104 AC: 9 AN: 865956 Hom.: 0 Cov.: 30 AF XY: 0.00000495 AC XY: 2 AN XY: 404410

African (AFR) AF: 0.000549 AC: 9 AN: 16394

American (AMR) AF: 0.00 AC: 0 AN: 1998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5860

East Asian (EAS) AF: 0.00 AC: 0 AN: 5044

South Asian (SAS) AF: 0.00 AC: 0 AN: 17556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1772

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 785010

Other (OTH) AF: 0.00 AC: 0 AN: 29084

GnomAD4 genome AF: 0.0000673 AC: 10 AN: 148500 Hom.: 0 Cov.: 32 AF XY: 0.0000552 AC XY: 4 AN XY: 72432

African (AFR) AF: 0.000219 AC: 9 AN: 41172

American (AMR) AF: 0.0000670 AC: 1 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3426

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: 9150

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66600

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.8
DANN	Benign	0.94
DEOGEN2	Benign	0.059	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-3.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.013
Sift	Benign	0.13	T
Sift4G	Benign	0.19	T
Polyphen		0.10	B
Vest4		0.14
MutPred		0.24		Gain of glycosylation at S10 (P = 0.0217)
MVP		0.22
ClinPred		0.097	T
GERP RS		-4.2
PromoterAI		0.0039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.061
gMVP		0.15
Mutation Taster		=99/1	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: rs939779373; hg19: chr4-5713121;