19-41121476-C-A

Variant names:

• chr19-41121476-C-A
• rs1288556893
• NM_000774.5:c.503C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000774.5(CYP2F1):​c.503C>A​(p.Thr168Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYP2F1 NM_000774.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.871

Genes affected

CYP2F1 (HGNC:2632): (cytochrome P450 family 2 subfamily F 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 protein localizes to the endoplasmic reticulum and is known to dehydrogenate 3-methylindole, an endogenous toxin derived from the fermentation of tryptophan, as well as xenobiotic substrates such as naphthalene and ethoxycoumarin. This gene is part of a large cluster of cytochrome P450 genes from the CYP2A, CYP2B and CYP2F subfamilies on chromosome 19q. [provided by RefSeq, Jul 2008]

ACMG classification

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=0.21147284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2F1	NM_000774.5	c.503C>A	p.Thr168Lys	missense_variant	Exon 5 of 10	ENST00000331105.7	NP_000765.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2F1	ENST00000331105.7	c.503C>A	p.Thr168Lys	missense_variant	Exon 5 of 10	1	NM_000774.5	ENSP00000333534.2
CYP2F1	ENST00000532164.2	n.503C>A		non_coding_transcript_exon_variant	Exon 5 of 10	1		ENSP00000471416.1
CYP2F1	ENST00000531409.5	n.578C>A		non_coding_transcript_exon_variant	Exon 5 of 8	2
CYP2F1	ENST00000526093.5	n.225-481C>A		intron_variant	Intron 2 of 3	4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250472 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135414

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459904 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726338

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.503C>A (p.T168K) alteration is located in exon 5 (coding exon 4) of the CYP2F1 gene. This alteration results from a C to A substitution at nucleotide position 503, causing the threonine (T) at amino acid position 168 to be replaced by a lysine (K). 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	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.13
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.12	T
Polyphen		0.53	P
Vest4		0.17
MutPred		0.65		Gain of methylation at T168 (P = 0.0101);
MVP		0.74
MPC		0.41
ClinPred		0.62	D
GERP RS		0.74
Varity_R		0.35
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1288556893; hg19: chr19-41627381;