Genetic Variant CYP2U1:p.Met1fs (chr4-107931619-ACCCGAGGCCGCCGGCGCCCGGACCATGTCGTC-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_Moderate

The NM_183075.3(CYP2U1):c.-24_8delCCCGAGGCCGCCGGCGCCCGGACCATGTCGTC(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,098,042 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

CYP2U1
NM_183075.3 frameshift, start_lost

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.43

Publications

0 publications found

Variant links:

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 links:

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

CYP2U1-AS1 links:

LOC107986298 (HGNC:):

LOC107986298 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 54 pathogenic variants in the truncated region.

PP5

Variant 4-107931619-ACCCGAGGCCGCCGGCGCCCGGACCATGTCGTC-A is Pathogenic according to our data. Variant chr4-107931619-ACCCGAGGCCGCCGGCGCCCGGACCATGTCGTC-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 445958.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2U1	NM_183075.3 link	c.-24_8delCCCGAGGCCGCCGGCGCCCGGACCATGTCGTC	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 5	ENST00000332884.11	NP_898898.1	Q7Z449-1
CYP2U1	NM_183075.3 link	c.-24_8delCCCGAGGCCGCCGGCGCCCGGACCATGTCGTC		5_prime_UTR_variant	Exon 1 of 5	ENST00000332884.11	NP_898898.1	Q7Z449-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2U1	ENST00000332884.11 link	c.-24_8delCCCGAGGCCGCCGGCGCCCGGACCATGTCGTC	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 5	1	NM_183075.3	ENSP00000333212.6		Q7Z449-1
CYP2U1	ENST00000332884.11 link	c.-24_8delCCCGAGGCCGCCGGCGCCCGGACCATGTCGTC		5_prime_UTR_variant	Exon 1 of 5	1	NM_183075.3	ENSP00000333212.6		Q7Z449-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000255

AC:

AN:

1098042

Hom.:

AF XY:

0.0000287

AC XY:

AN XY:

521950

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23088

American (AMR)

AF:

0.00

AC:

AN:

8558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13968

East Asian (EAS)

AF:

0.00

AC:

AN:

26684

South Asian (SAS)

AF:

0.00

AC:

AN:

23312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2922

European-Non Finnish (NFE)

AF:

0.0000300

AC:

AN:

932912

Other (OTH)

AF:

0.00

AC:

AN:

44068

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

May 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over