19-15922059-G-T

Position:

• chr19-15922059-G-T

Variant summary

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

The NM_021187.4(CYP4F11):​c.1093C>A​(p.Arg365Ser) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CYP4F11 NM_021187.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

Genes affected

CYP4F11 (HGNC:13265): (cytochrome P450 family 4 subfamily F member 11) This gene, CYP4F11, 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 gene is part of a cluster of cytochrome P450 genes on chromosome 19. Another member of this family, CYP4F2, is approximately 16 kb away. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [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=0.19866452).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP4F11	NM_021187.4	c.1093C>A	p.Arg365Ser	missense_variant	8/12	ENST00000402119.9	NP_067010.3
CYP4F11	NM_001128932.2	c.1093C>A	p.Arg365Ser	missense_variant	9/13		NP_001122404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP4F11	ENST00000402119.9	c.1093C>A	p.Arg365Ser	missense_variant	8/12	1	NM_021187.4	ENSP00000384588.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2023

The c.1093C>A (p.R365S) alteration is located in exon 8 (coding exon 8) of the CYP4F11 gene. This alteration results from a C to A substitution at nucleotide position 1093, causing the arginine (R) at amino acid position 365 to be replaced by a serine (S). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.24	.;T;.;T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.69	.;.;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.6	.;L;.;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.2	D;D;.;D;.
REVEL	Benign	0.086
Sift	Uncertain	0.0050	D;D;.;D;.
Sift4G	Uncertain	0.018	D;D;D;D;T
Polyphen		0.078	B;P;B;P;.
Vest4		0.42
MutPred		0.35		Gain of phosphorylation at R365 (P = 0.0576);Gain of phosphorylation at R365 (P = 0.0576);Gain of phosphorylation at R365 (P = 0.0576);Gain of phosphorylation at R365 (P = 0.0576);.;
MVP		0.49
MPC		0.094
ClinPred		0.84	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.84
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs142513893; hg19: chr19-16032869;