4-107932095-C-T

Variant names:

• chr4-107932095-C-T
• rs761575210
• ENST00000508453.1:c.-374C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The ENST00000508453.1(CYP2U1):​c.-374C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000138 in 1,446,890 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYP2U1 ENST00000508453.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.66
• Publications: 2 publications found

Genes affected

CYP2U1 (HGNC:20582): (cytochrome P450 family 2 subfamily U member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This enzyme is a hydroxylase that metabolizes arachidonic acid, docosahexaenoic acid, and other long chain fatty acids. [provided by RefSeq, Jul 2008]

CYP2U1-AS1 (HGNC:54817): (CYP2U1 and SGMS2 antisense RNA 1)

LOC107986298 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• PP5: Variant 4-107932095-C-T is Pathogenic according to our data. Variant chr4-107932095-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 433182.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000508453.1. 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
	CYP2U1	NM_183075.3	MANE Select	c.452C>T	p.Pro151Leu	missense	Exon 1 of 5	NP_898898.1	Q7Z449-1
	CYP2U1-AS1	NR_125929.1		n.25G>A		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2U1	ENST00000508453.1	TSL:1	c.-374C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000423667.1	E9PGH5
	CYP2U1	ENST00000332884.11	TSL:1 MANE Select	c.452C>T	p.Pro151Leu	missense	Exon 1 of 5	ENSP00000333212.6	Q7Z449-1
	CYP2U1	ENST00000508453.1	TSL:1	c.-374C>T		5_prime_UTR	Exon 1 of 7	ENSP00000423667.1	E9PGH5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446890 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 718384

African (AFR) AF: 0.00 AC: 0 AN: 33114

American (AMR) AF: 0.00 AC: 0 AN: 43058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25846

East Asian (EAS) AF: 0.00 AC: 0 AN: 38710

South Asian (SAS) AF: 0.00 AC: 0 AN: 83588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105966

Other (OTH) AF: 0.00 AC: 0 AN: 59760

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary spastic paraplegia 56 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-8.2	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.70		Loss of relative solvent accessibility (P = 0.0981)
MVP		0.87
MPC		0.63
ClinPred		1.0	D
GERP RS		3.6
PromoterAI		0.032	Neutral
Varity_R		0.77
gMVP		0.78
Mutation Taster		=41/59	disease causing (ClinVar)

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: rs761575210; hg19: chr4-108853251;