rs142676629

chr4-107947400-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_183075.3(CYP2U1):c.1151G>T(p.Arg384Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,614,088 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R384G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (5 hom.)
• Consequence: CYP2U1 NM_183075.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.335

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011860281).
• BP6: Variant 4-107947400-G-T is Benign according to our data. Variant chr4-107947400-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 458307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0021 (320/152246) while in subpopulation NFE AF= 0.00347 (236/68000). AF 95% confidence interval is 0.00311. There are 0 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2U1	NM_183075.3	c.1151G>T	p.Arg384Ile	missense_variant	3/5	ENST00000332884.11
LOC107986298	XR_001741784.2	n.204+31320C>A		intron_variant, non_coding_transcript_variant
CYP2U1	XM_005262717.2	c.1205G>T	p.Arg402Ile	missense_variant	3/5
CYP2U1	XM_005262720.2	c.515G>T	p.Arg172Ile	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2U1	ENST00000332884.11	c.1151G>T	p.Arg384Ile	missense_variant	3/5	1	NM_183075.3	P1
CYP2U1-AS1	ENST00000656249.1	n.80+31320C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 320 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00347

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00248 AC: 622 AN: 251234 Hom.: 2 AF XY: 0.00252 AC XY: 342 AN XY: 135788

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00403

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00295 AC: 4307 AN: 1461842 Hom.: 5 Cov.: 33 AF XY: 0.00287 AC XY: 2085 AN XY: 727226

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00406

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.000805

Gnomad4 NFE exome AF: 0.00350

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00210 AC: 320 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74462

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00347

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00392 Hom.: 2

Bravo AF: 0.00237

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00240 AC: 291

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00442

EpiControl AF: 0.00533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2020	This variant is associated with the following publications: (PMID: 29034544, 30564185, 32006740) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CYP2U1: BP4, BS2 -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 16, 2021

- -

CYP2U1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Benign	0.34	T;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	0.96	D;D
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.27
Sift	Benign	0.13	T;D
Sift4G	Benign	0.17	T;T
Polyphen		0.58	P;.
Vest4		0.56
MVP		0.77
MPC		0.38
ClinPred		0.045	T
GERP RS		3.0
Varity_R		0.22
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs142676629; hg19: chr4-108868556;