19-15913820-G-A

Position:

• chr19-15913820-G-A

Variant summary

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

The NM_021187.4(CYP4F11):​c.1487C>T​(p.Thr496Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,870 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 (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CYP4F11 NM_021187.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.19

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=0.15976843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP4F11	NM_021187.4	c.1487C>T	p.Thr496Ile	missense_variant	12/12	ENST00000402119.9	NP_067010.3
CYP4F11	NM_001128932.2	c.1487C>T	p.Thr496Ile	missense_variant	13/13		NP_001122404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP4F11	ENST00000402119.9	c.1487C>T	p.Thr496Ile	missense_variant	12/12	1	NM_021187.4	ENSP00000384588	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461870 Hom.: 0 Cov.: 65 AF XY: 0.00000550 AC XY: 4 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

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

Nov 09, 2023

The c.1487C>T (p.T496I) alteration is located in exon 12 (coding exon 12) of the CYP4F11 gene. This alteration results from a C to T substitution at nucleotide position 1487, causing the threonine (T) at amino acid position 496 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	0.092
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.026
DANN	Benign	0.88
DEOGEN2	Benign	0.054	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.030	.;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.7	D;D;.
REVEL	Benign	0.15
Sift	Benign	0.13	T;T;.
Sift4G	Benign	0.17	T;T;T
Polyphen		0.075	B;B;.
Vest4		0.16
MutPred		0.39		Gain of catalytic residue at P498 (P = 0.0312);Gain of catalytic residue at P498 (P = 0.0312);.;
MVP		0.40
MPC		0.031
ClinPred		0.19	T
GERP RS		-1.6
Varity_R		0.066
gMVP		0.42

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: rs752488247; hg19: chr19-16024630;