4-186191863-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_207352.4(CYP4V2):c.40C>G(p.Leu14Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000883 in 1,585,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CYP4V2 NM_207352.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.344

Genes affected

CYP4V2 (HGNC:23198): (cytochrome P450 family 4 subfamily V member 2) This gene encodes a member of the cytochrome P450 hemethiolate protein superfamily which are involved in oxidizing various substrates in the metabolic pathway. It is implicated in the metabolism of fatty acid precursors into n-3 polyunsaturated fatty acids. Mutations in this gene result in Bietti crystalline corneoretinal dystrophy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27196908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP4V2	NM_207352.4	c.40C>G	p.Leu14Val	missense_variant	1/11	ENST00000378802.5
CYP4V2	XM_005262935.5	c.40C>G	p.Leu14Val	missense_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4V2	ENST00000378802.5	c.40C>G	p.Leu14Val	missense_variant	1/11	1	NM_207352.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00000349 AC: 5 AN: 1433074 Hom.: 0 Cov.: 30 AF XY: 0.00000281 AC XY: 2 AN XY: 711490

Gnomad4 AFR exome AF: 0.0000608

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000337

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74328

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000718

ExAC AF: 0.0000169 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2021

The c.40C>G (p.L14V) alteration is located in exon 1 (coding exon 1) of the CYP4V2 gene. This alteration results from a C to G substitution at nucleotide position 40, causing the leucine (L) at amino acid position 14 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 13, 2022

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 14 of the CYP4V2 protein (p.Leu14Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CYP4V2 protein function. ClinVar contains an entry for this variant (Variation ID: 1026579). This variant has not been reported in the literature in individuals affected with CYP4V2-related conditions. This variant is present in population databases (rs763159414, gnomAD 0.02%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	0.97	N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.11
Sift	Benign	0.22	T
Sift4G	Benign	0.15	T
Polyphen		0.60	P
Vest4		0.24
MutPred		0.46		Gain of MoRF binding (P = 0.0765);
MVP		0.65
MPC		0.11
ClinPred		0.25	T
GERP RS		0.58
Varity_R		0.049
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs763159414; hg19: chr4-187113017;