rs147506864

Positions:

• chr4-107931951-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000508453(CYP2U1):​c.-518C>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 0.00108 in 1,551,504 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: CYP2U1 ENST00000508453 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.200

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01012817).
• BP6: Variant 4-107931951-C-T is Benign according to our data. Variant chr4-107931951-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409955.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00122 (186/152320) while in subpopulation AMR AF= 0.00229 (35/15302). AF 95% confidence interval is 0.00169. There are 1 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2U1	NM_183075.3	c.308C>T	p.Pro103Leu	missense_variant	1/5	ENST00000332884.11	NP_898898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2U1	ENST00000332884.11	c.308C>T	p.Pro103Leu	missense_variant	1/5	1	NM_183075.3	ENSP00000333212.6

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 152202 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00120 AC: 187 AN: 155382 Hom.: 0 AF XY: 0.00112 AC XY: 92 AN XY: 82164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000395

Gnomad FIN exome AF: 0.000130

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.00227

GnomAD4 exome AF: 0.00107 AC: 1496 AN: 1399184 Hom.: 3 Cov.: 31 AF XY: 0.00106 AC XY: 735 AN XY: 690186

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000341

Gnomad4 FIN exome AF: 0.0000818

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.000621

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152320 Hom.: 1 Cov.: 33 AF XY: 0.000994 AC XY: 74 AN XY: 74484

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.00140

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00217 AC: 18

ExAC AF: 0.000436 AC: 43

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2019

- -

Hereditary spastic paraplegia 56 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 05, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 05, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 02, 2024

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.98	L
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.13
Sift	Benign	0.037	D
Sift4G	Benign	0.45	T
Polyphen		0.033	B
Vest4		0.10
MVP		0.37
MPC		0.15
ClinPred		0.026	T
GERP RS		0.80
Varity_R		0.056
gMVP		0.80

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: rs147506864; hg19: chr4-108853107;