4-186209242-C-T

Variant names:

• chr4-186209242-C-T
• rs1554075115
• NM_207352.4:c.1375C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_207352.4(CYP4V2):​c.1375C>T​(p.Pro459Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P459L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CYP4V2 NM_207352.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.07
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Bietti crystalline corneoretinal dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Illumina, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ENSG00000290316 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_207352.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: -0.12103 (below the threshold of 3.09). Trascript score misZ: -0.14191 (below the threshold of 3.09). GenCC associations: The gene is linked to Bietti crystalline corneoretinal dystrophy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207352.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4V2	NM_207352.4	MANE Select	c.1375C>T	p.Pro459Ser	missense	Exon 10 of 11	NP_997235.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4V2	ENST00000378802.5	TSL:1 MANE Select	c.1375C>T	p.Pro459Ser	missense	Exon 10 of 11	ENSP00000368079.4
	ENSG00000290316	ENST00000511608.5	TSL:5	c.169C>T	p.Pro57Ser	missense	Exon 2 of 15	ENSP00000426629.1
	CYP4V2	ENST00000502665.1	TSL:1	n.610C>T		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.93		Gain of glycosylation at Y455 (P = 0.0037)
MVP		0.98
MPC		0.41
ClinPred		1.0	D
GERP RS		5.4
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.90
Mutation Taster		=13/87	disease causing

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

Other links and lift over

dbSNP: rs1554075115; hg19: chr4-187130396; COSMIC: COSV66504950;