rs1407007311

Variant names:

• chr4-5729370-C-A
• NM_153717.3:c.364C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-5729370-C-A
• chr4-5729370-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_153717.3(EVC):​c.364C>A​(p.Pro122Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P122S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.46

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-5729370-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC	NM_153717.3	c.364C>A	p.Pro122Thr	missense_variant	Exon 3 of 21	ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11	c.364C>A	p.Pro122Thr	missense_variant	Exon 3 of 21	1	NM_153717.3	ENSP00000264956.6
EVC	ENST00000509451.1	c.364C>A	p.Pro122Thr	missense_variant	Exon 3 of 12	1		ENSP00000426774.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.44		Loss of catalytic residue at P122 (P = 0.0172);Loss of catalytic residue at P122 (P = 0.0172);
MVP		0.93
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.82
gMVP		0.49

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-5731097;