chr4-186191953-T-C

Variant names:

• chr4-186191953-T-C
• rs119103282
• NM_207352.4:c.130T>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1 PM2 PP3_Strong

The NM_207352.4(CYP4V2):​c.130T>C​(p.Trp44Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000209 in 1,436,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CYP4V2 NM_207352.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.02

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 Pathogenic. Variant got 10 ACMG points.

• PS1: Transcript NM_207352.4 (CYP4V2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP4V2	NM_207352.4	c.130T>C	p.Trp44Arg	missense_variant	Exon 1 of 11	ENST00000378802.5	NP_997235.3
CYP4V2	XM_005262935.5	c.130T>C	p.Trp44Arg	missense_variant	Exon 1 of 11		XP_005262992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP4V2	ENST00000378802.5	c.130T>C	p.Trp44Arg	missense_variant	Exon 1 of 11	1	NM_207352.4	ENSP00000368079.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000997 AC: 2 AN: 200594 Hom.: 0 AF XY: 0.00000912 AC XY: 1 AN XY: 109630

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000749

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1436134 Hom.: 0 Cov.: 32 AF XY: 0.00000281 AC XY: 2 AN XY: 712826

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000241

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000839 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Benign	0.78
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.43
Sift	Benign	0.51	T
Sift4G	Benign	0.41	T
Polyphen		0.0020	B
Vest4		0.95
MutPred		0.79		Gain of disorder (P = 0.0016);
MVP		0.81
MPC		0.13
ClinPred		0.57	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.62
gMVP		0.86

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: rs119103282; hg19: chr4-187113107;