rs34745240

Positions:

• chr4-186201178-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_207352.4(CYP4V2):​c.823G>A​(p.Glu275Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0294 in 1,613,724 control chromosomes in the GnomAD database, including 861 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (145 hom., cov: 31)
  • Exomes 𝑓: 0.029 (716 hom.)
• Consequence: CYP4V2 NM_207352.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.03

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023715794).
• BP6: Variant 4-186201178-G-A is Benign according to our data. Variant chr4-186201178-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 263298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186201178-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP4V2	NM_207352.4	c.823G>A	p.Glu275Lys	missense_variant	7/11	ENST00000378802.5	NP_997235.3
CYP4V2	XM_005262935.5	c.823G>A	p.Glu275Lys	missense_variant	7/11		XP_005262992.1
CYP4V2	XM_047450077.1	c.427G>A	p.Glu143Lys	missense_variant	5/9		XP_047306033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP4V2	ENST00000378802.5	c.823G>A	p.Glu275Lys	missense_variant	7/11	1	NM_207352.4	ENSP00000368079	P1
CYP4V2	ENST00000507209.5	n.1664G>A		non_coding_transcript_exon_variant	3/6	1

Frequencies

GnomAD3 genomes AF: 0.0376 AC: 5714 AN: 152156 Hom.: 146 Cov.: 31

Gnomad AFR AF: 0.0641

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0323

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00643

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0300

Gnomad OTH AF: 0.0459

GnomAD3 exomes AF: 0.0262 AC: 6590 AN: 251296 Hom.: 121 AF XY: 0.0255 AC XY: 3457 AN XY: 135822

Gnomad AFR exome AF: 0.0661

Gnomad AMR exome AF: 0.0211

Gnomad ASJ exome AF: 0.0389

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00853

Gnomad FIN exome AF: 0.0190

Gnomad NFE exome AF: 0.0310

Gnomad OTH exome AF: 0.0316

GnomAD4 exome AF: 0.0285 AC: 41665 AN: 1461450 Hom.: 716 Cov.: 34 AF XY: 0.0278 AC XY: 20194 AN XY: 727028

Gnomad4 AFR exome AF: 0.0662

Gnomad4 AMR exome AF: 0.0225

Gnomad4 ASJ exome AF: 0.0414

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00854

Gnomad4 FIN exome AF: 0.0186

Gnomad4 NFE exome AF: 0.0300

Gnomad4 OTH exome AF: 0.0316

GnomAD4 genome AF: 0.0375 AC: 5711 AN: 152274 Hom.: 145 Cov.: 31 AF XY: 0.0360 AC XY: 2680 AN XY: 74456

Gnomad4 AFR AF: 0.0639

Gnomad4 AMR AF: 0.0323

Gnomad4 ASJ AF: 0.0389

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00643

Gnomad4 FIN AF: 0.0200

Gnomad4 NFE AF: 0.0300

Gnomad4 OTH AF: 0.0450

Alfa AF: 0.0319 Hom.: 133

Bravo AF: 0.0400

TwinsUK AF: 0.0272 AC: 101

ALSPAC AF: 0.0267 AC: 103

ESP6500AA AF: 0.0574 AC: 253

ESP6500EA AF: 0.0288 AC: 248

ExAC AF: 0.0272 AC: 3302

Asia WGS AF: 0.00924 AC: 36 AN: 3478

EpiCase AF: 0.0333

EpiControl AF: 0.0348

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Bietti crystalline corneoretinal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Corneal dystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.073
Sift	Benign	0.10	T
Sift4G	Benign	0.33	T
Polyphen		0.080	B
Vest4		0.031
MPC		0.081
ClinPred		0.0065	T
GERP RS		3.8
Varity_R		0.21
gMVP		0.39

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: rs34745240; hg19: chr4-187122332;