chr4-186192020-T-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_207352.4(CYP4V2):c.197T>G(p.Met66Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000221 in 1,581,278 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 (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
CYP4V2
NM_207352.4 missense
NM_207352.4 missense
Scores
5
6
8
Clinical Significance
Conservation
PhyloP100: 3.50
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 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, 6 uncertain in NM_207352.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.972
PP5
?
Variant 4-186192020-T-G is Pathogenic according to our data. Variant chr4-186192020-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 438149.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-186192020-T-G is described in Lovd as [Pathogenic]. Variant chr4-186192020-T-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP4V2 | NM_207352.4 | c.197T>G | p.Met66Arg | missense_variant | 1/11 | ENST00000378802.5 | |
CYP4V2 | XM_005262935.5 | c.197T>G | p.Met66Arg | missense_variant | 1/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP4V2 | ENST00000378802.5 | c.197T>G | p.Met66Arg | missense_variant | 1/11 | 1 | NM_207352.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152130Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000413 AC: 8AN: 193478Hom.: 0 AF XY: 0.0000563 AC XY: 6AN XY: 106498
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GnomAD4 exome AF: 0.0000231 AC: 33AN: 1429148Hom.: 0 Cov.: 32 AF XY: 0.0000367 AC XY: 26AN XY: 709202
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 24, 2023 | For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP4V2 protein function. ClinVar contains an entry for this variant (Variation ID: 438149). This missense change has been observed in individual(s) with CYP4V2-related conditions (PMID: 24480711, 28041643). This variant is present in population databases (rs745413794, gnomAD 0.03%). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 66 of the CYP4V2 protein (p.Met66Arg). - |
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MutPred
Gain of methylation at M66 (P = 0.0279);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at