chr4-107931750-C-A

Position:

• chr4-107931750-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_183075.3(CYP2U1):​c.107C>A​(p.Ala36Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000391 in 1,278,244 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A36A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000039 (0 hom.)
• Consequence: CYP2U1 NM_183075.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.542

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41181847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2U1	NM_183075.3	c.107C>A	p.Ala36Glu	missense_variant	1/5	ENST00000332884.11
CYP2U1-AS1	NR_125929.1	n.149+221G>T		intron_variant, non_coding_transcript_variant
LOC107986298	XR_001741784.2	n.205-21201G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2U1	ENST00000332884.11	c.107C>A	p.Ala36Glu	missense_variant	1/5	1	NM_183075.3	P1
CYP2U1-AS1	ENST00000656249.1	n.81-21201G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000391 AC: 5 AN: 1278244 Hom.: 0 Cov.: 30 AF XY: 0.00000480 AC XY: 3 AN XY: 625256

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000161

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000387

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CYP2U1 protein function. ClinVar contains an entry for this variant (Variation ID: 1494421). This variant has not been reported in the literature in individuals affected with CYP2U1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 36 of the CYP2U1 protein (p.Ala36Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	0.0017	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.059
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	D;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.34
Sift	Benign	0.34	T
Sift4G	Benign	0.30	T
Polyphen		1.0	D
Vest4		0.40
MutPred		0.50		Loss of glycosylation at S33 (P = 0.1285);
MVP		0.73
MPC		2.9
ClinPred		0.43	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.56

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: rs1351893573; hg19: chr4-108852906;