4-186208943-G-A

Position:

• chr4-186208943-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_207352.4(CYP4V2):​c.1169G>A​(p.Arg390His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R390C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: CYP4V2 NM_207352.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 9.82

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]

CYP4V2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-186208942-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 4-186208943-G-A is Pathogenic according to our data. Variant chr4-186208943-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 39251.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-186208943-G-A is described in Lovd as [Pathogenic]. Variant chr4-186208943-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP4V2	NM_207352.4	c.1169G>A	p.Arg390His	missense_variant	9/11	ENST00000378802.5	NP_997235.3
CYP4V2	XM_005262935.5	c.1169G>A	p.Arg390His	missense_variant	9/11		XP_005262992.1
CYP4V2	XM_047450077.1	c.773G>A	p.Arg258His	missense_variant	7/9		XP_047306033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP4V2	ENST00000378802.5	c.1169G>A	p.Arg390His	missense_variant	9/11	1	NM_207352.4	ENSP00000368079.4
ENSG00000290316	ENST00000511608.5	c.-38G>A		upstream_gene_variant		5		ENSP00000426629.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251490 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461894 Hom.: 0 Cov.: 39 AF XY: 0.0000124 AC XY: 9 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000611 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 10, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 390 of the CYP4V2 protein (p.Arg390His). This variant is present in population databases (rs199476201, gnomAD 0.01%). This missense change has been observed in individual(s) with Bietti crystalline corneoretinal dystrophy (PMID: 21565171, 33090715). ClinVar contains an entry for this variant (Variation ID: 39251). 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 expected to disrupt CYP4V2 protein function. This variant disrupts the p.Arg390 amino acid residue in CYP4V2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22087103, 26971461, 28051075). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Bietti crystalline corneoretinal dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

Apr 12, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MVP		0.99
MPC		0.45
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs199476201; hg19: chr4-187130097; COSMIC: COSV101114927; COSMIC: COSV101114927;