4-186191691-G-T

Variant names:

• chr4-186191691-G-T
• rs562885669
• NM_207352.4:c.-133G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_207352.4(CYP4V2):​c.-133G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 855,806 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (3 hom.)
• Consequence: CYP4V2 NM_207352.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -2.29
• Publications: 1 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, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Illumina, G2P

FLJ38576 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000297 (209/703992) while in subpopulation EAS AF = 0.0095 (207/21792). AF 95% confidence interval is 0.00844. There are 3 homozygotes in GnomAdExome4. There are 101 alleles in the male GnomAdExome4 subpopulation. Median coverage is 9. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.-133G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_997235.3	Q6ZWL3-1
	CYP4V2	NM_207352.4	MANE Select	c.-133G>T		5_prime_UTR	Exon 1 of 11	NP_997235.3	Q6ZWL3-1
	FLJ38576	NR_046264.1		n.-201C>A		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4V2	ENST00000378802.5	TSL:1 MANE Select	c.-133G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000368079.4	Q6ZWL3-1
	CYP4V2	ENST00000378802.5	TSL:1 MANE Select	c.-133G>T		5_prime_UTR	Exon 1 of 11	ENSP00000368079.4	Q6ZWL3-1
	CYP4V2	ENST00000905174.1		c.-133G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000575233.1

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 9 AN: 151712 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000297 AC: 209 AN: 703992 Hom.: 3 Cov.: 9 AF XY: 0.000298 AC XY: 101 AN XY: 338978

African (AFR) AF: 0.00 AC: 0 AN: 14904

American (AMR) AF: 0.00 AC: 0 AN: 6946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10644

East Asian (EAS) AF: 0.00950 AC: 207 AN: 21792

South Asian (SAS) AF: 0.00 AC: 0 AN: 13158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2142

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 583348

Other (OTH) AF: 0.0000662 AC: 2 AN: 30212

GnomAD4 genome AF: 0.0000593 AC: 9 AN: 151814 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74216

African (AFR) AF: 0.00 AC: 0 AN: 41352

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00175 AC: 9 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67912

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Bietti crystalline corneoretinal dystrophy (1)
-	1	-	Corneal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.13
DANN	Benign	0.76
PhyloP100		-2.3
PromoterAI		-0.057	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs562885669; hg19: chr4-187112845;