4-107931644-A-T

Variant names:

• chr4-107931644-A-T
• rs773841071
• ENST00000508453.1:c.-825A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000508453.1(CYP2U1):​c.-825A>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 0.000000905 in 1,105,060 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.0e-7 (0 hom.)
• Consequence: CYP2U1 ENST00000508453.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.17
• Publications: 0 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, 0.992

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.1A>T	p.Met1?	initiator_codon	Exon 1 of 5	NP_898898.1	Q7Z449-1
	CYP2U1-AS1	NR_125929.1		n.149+327T>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2U1	ENST00000508453.1	TSL:1	c.-825A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000423667.1	E9PGH5
	CYP2U1	ENST00000332884.11	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 5	ENSP00000333212.6	Q7Z449-1
	CYP2U1	ENST00000508453.1	TSL:1	c.-825A>T		5_prime_UTR	Exon 1 of 7	ENSP00000423667.1	E9PGH5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.05e-7 AC: 1 AN: 1105060 Hom.: 0 Cov.: 30 AF XY: 0.00000190 AC XY: 1 AN XY: 526400

African (AFR) AF: 0.00 AC: 0 AN: 22852

American (AMR) AF: 0.00 AC: 0 AN: 8242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14218

East Asian (EAS) AF: 0.0000381 AC: 1 AN: 26274

South Asian (SAS) AF: 0.00 AC: 0 AN: 26010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2944

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 937122

Other (OTH) AF: 0.00 AC: 0 AN: 44330

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.088	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.28	T
PhyloP100		2.2
PROVEAN	Benign	-0.38	N
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.70	P
Vest4		0.91
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.1148)
MVP		0.82
ClinPred		0.99	D
GERP RS		4.2
PromoterAI		-0.14	Neutral
Varity_R		0.92
gMVP		0.30
Mutation Taster		=20/180	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: rs773841071; hg19: chr4-108852800;