4-107945263-T-G

Variant names:

• chr4-107945263-T-G
• rs397514515
• NM_183075.3:c.784T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_183075.3(CYP2U1):​c.784T>G​(p.Cys262Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C262R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CYP2U1 NM_183075.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-107945263-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27743852).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183075.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2U1	NM_183075.3	MANE Select	c.784T>G	p.Cys262Gly	missense	Exon 2 of 5	NP_898898.1	Q7Z449-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2U1	ENST00000332884.11	TSL:1 MANE Select	c.784T>G	p.Cys262Gly	missense	Exon 2 of 5	ENSP00000333212.6	Q7Z449-1
	CYP2U1	ENST00000508453.1	TSL:1	c.157T>G	p.Cys53Gly	missense	Exon 4 of 7	ENSP00000423667.1	E9PGH5
	CYP2U1	ENST00000908818.1		c.736+48T>G		intron	N/A	ENSP00000578877.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.42	N
PhyloP100		2.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.18
Sift	Benign	0.44	T
Sift4G	Benign	0.39	T
Polyphen		0.0010	B
Vest4		0.48
MutPred		0.52		Loss of stability (P = 0.0069)
MVP		0.57
MPC		0.27
ClinPred		0.68	D
GERP RS		4.4
Varity_R		0.17
gMVP		0.51
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs397514515; hg19: chr4-108866419;