rs149684063

Positions:

• chr4-186196042-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_207352.4(CYP4V2):​c.367A>G​(p.Met123Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000421 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: CYP4V2 NM_207352.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:7 B:2
• Conservation: PhyloP100: -2.37

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17114612).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000276 (42/152334) while in subpopulation EAS AF= 0.0054 (28/5184). AF 95% confidence interval is 0.00384. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP4V2	NM_207352.4	c.367A>G	p.Met123Val	missense_variant	3/11	ENST00000378802.5	NP_997235.3
CYP4V2	XM_005262935.5	c.367A>G	p.Met123Val	missense_variant	3/11		XP_005262992.1
CYP4V2	XM_047450077.1	c.18-898A>G		intron_variant			XP_047306033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP4V2	ENST00000378802.5	c.367A>G	p.Met123Val	missense_variant	3/11	1	NM_207352.4	ENSP00000368079.4
CYP4V2	ENST00000507209.5	n.-46A>G		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00539

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000792 AC: 199 AN: 251406 Hom.: 0 AF XY: 0.000758 AC XY: 103 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00875

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000436 AC: 638 AN: 1461758 Hom.: 0 Cov.: 30 AF XY: 0.000395 AC XY: 287 AN XY: 727172

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00778

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74490

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00540

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000392 Hom.: 0

Bravo AF: 0.000476

ExAC AF: 0.000700 AC: 85

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bietti crystalline corneoretinal dystrophy Pathogenic:1 Uncertain:3

Pathogenic, no assertion criteria provided	curation	GeneReviews	Apr 12, 2012	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The CYP4V2 c.367A>G (p.Met123Val) missense variant has been reported in a compound heterozygous state in one individual with Bietti crystalline dystrophy (Li et al. 2004). The p.Met123Val variant was absent from 100 controls but is reported at a frequency of 0.00496 in the East Asian population of the 1000 Genomes Project. The evidence for this variant is limited. The p.Met123Val variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Bietti crystalline dystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.074%). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CYP4V2-related disorder (PMID: 15042513). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

Retinal dystrophy Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 03, 2019	- -

not provided Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -

Corneal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	0.013
DANN	Benign	0.47
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.47	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.19	N
REVEL	Uncertain	0.48
Sift	Benign	0.43	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.72
MVP		0.41
MPC		0.069
ClinPred		0.019	T
GERP RS		-5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.036
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs149684063; hg19: chr4-187117196;