chr4-107931741-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_183075.3(CYP2U1):​c.98G>T​(p.Ser33Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,422,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. S33S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

CYP2U1
NM_183075.3 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.706
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-AS1 (HGNC:54817): (CYP2U1 and SGMS2 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.09097099).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CYP2U1NM_183075.3 linkuse as main transcriptc.98G>T p.Ser33Ile missense_variant 1/5 ENST00000332884.11
CYP2U1-AS1NR_125929.1 linkuse as main transcriptn.149+230C>A intron_variant, non_coding_transcript_variant
LOC107986298XR_001741784.2 linkuse as main transcriptn.205-21192C>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYP2U1ENST00000332884.11 linkuse as main transcriptc.98G>T p.Ser33Ile missense_variant 1/51 NM_183075.3 P1Q7Z449-1
CYP2U1-AS1ENST00000656249.1 linkuse as main transcriptn.81-21192C>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
151976
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000821
AC:
3
AN:
36542
Hom.:
0
AF XY:
0.0000965
AC XY:
2
AN XY:
20736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000532
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000323
AC:
41
AN:
1270488
Hom.:
0
Cov.:
30
AF XY:
0.0000338
AC XY:
21
AN XY:
621086
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000116
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000262
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000194
Gnomad4 OTH exome
AF:
0.0000570
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152084
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Bravo
AF:
0.000136

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 25, 2022This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 33 of the CYP2U1 protein (p.Ser33Ile). This variant is present in population databases (no rsID available, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with CYP2U1-related conditions. 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. 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. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 14, 2023The c.98G>T (p.S33I) alteration is located in exon 1 (coding exon 1) of the CYP2U1 gene. This alteration results from a G to T substitution at nucleotide position 98, causing the serine (S) at amino acid position 33 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
8.6
DANN
Benign
0.95
DEOGEN2
Benign
0.11
T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.024
N
LIST_S2
Benign
0.49
T
M_CAP
Pathogenic
0.32
D
MetaRNN
Benign
0.091
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
1.0
L
MutationTaster
Benign
1.0
N;N
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.058
Sift
Uncertain
0.029
D
Sift4G
Benign
0.11
T
Polyphen
0.019
B
Vest4
0.17
MutPred
0.37
Loss of disorder (P = 0.0223);
MVP
0.20
MPC
1.7
ClinPred
0.023
T
GERP RS
-0.14
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.071
gMVP
0.39

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs970965477; hg19: chr4-108852897; API