19-15914366-C-T

Variant names:

• chr19-15914366-C-T
• rs1060463
• NM_021187.4:c.1336G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021187.4(CYP4F11):​c.1336G>A​(p.Asp446Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 1,613,380 control chromosomes in the GnomAD database, including 284,718 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D446H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.55 (23440 hom., cov: 30)
  • Exomes 𝑓: 0.59 (261278 hom.)
• Consequence: CYP4F11 NM_021187.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.456
• Publications: 57 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.642863E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021187.4. 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
	CYP4F11	NM_021187.4	MANE Select	c.1336G>A	p.Asp446Asn	missense	Exon 11 of 12	NP_067010.3	Q9HBI6
	CYP4F11	NM_001128932.2		c.1336G>A	p.Asp446Asn	missense	Exon 12 of 13	NP_001122404.1	Q9HBI6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4F11	ENST00000402119.9	TSL:1 MANE Select	c.1336G>A	p.Asp446Asn	missense	Exon 11 of 12	ENSP00000384588.2	Q9HBI6
	CYP4F11	ENST00000248041.12	TSL:1	c.1336G>A	p.Asp446Asn	missense	Exon 12 of 13	ENSP00000248041.6	Q9HBI6
	CYP4F11	ENST00000326742.12	TSL:1	c.1271G>A	p.Arg424Gln	missense	Exon 10 of 11	ENSP00000319859.7	F8W978

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83579 AN: 151792 Hom.: 23426 Cov.: 30

Gnomad AFR AF: 0.462

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.553

Gnomad FIN AF: 0.667

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.605

Gnomad OTH AF: 0.529

GnomAD2 exomes AF: 0.563 AC: 141549 AN: 251304 AF XY: 0.566

Gnomad AFR exome AF: 0.458

Gnomad AMR exome AF: 0.534

Gnomad ASJ exome AF: 0.515

Gnomad EAS exome AF: 0.410

Gnomad FIN exome AF: 0.658

Gnomad NFE exome AF: 0.602

Gnomad OTH exome AF: 0.569

GnomAD4 exome AF: 0.595 AC: 869157 AN: 1461468 Hom.: 261278 Cov.: 57 AF XY: 0.593 AC XY: 431445 AN XY: 727054

African (AFR) AF: 0.458 AC: 15329 AN: 33476

American (AMR) AF: 0.536 AC: 23940 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 13445 AN: 26128

East Asian (EAS) AF: 0.366 AC: 14521 AN: 39698

South Asian (SAS) AF: 0.548 AC: 47260 AN: 86244

European-Finnish (FIN) AF: 0.661 AC: 35321 AN: 53412

Middle Eastern (MID) AF: 0.512 AC: 2945 AN: 5754

European-Non Finnish (NFE) AF: 0.613 AC: 681280 AN: 1111684

Other (OTH) AF: 0.582 AC: 35116 AN: 60376

GnomAD4 genome AF: 0.551 AC: 83628 AN: 151912 Hom.: 23440 Cov.: 30 AF XY: 0.549 AC XY: 40722 AN XY: 74240

African (AFR) AF: 0.462 AC: 19150 AN: 41408

American (AMR) AF: 0.523 AC: 7992 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 1792 AN: 3472

East Asian (EAS) AF: 0.395 AC: 2028 AN: 5136

South Asian (SAS) AF: 0.552 AC: 2649 AN: 4798

European-Finnish (FIN) AF: 0.667 AC: 7046 AN: 10560

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.605 AC: 41129 AN: 67942

Other (OTH) AF: 0.526 AC: 1109 AN: 2108

Alfa AF: 0.576 Hom.: 106033

Bravo AF: 0.535

TwinsUK AF: 0.617 AC: 2289

ALSPAC AF: 0.601 AC: 2318

ESP6500AA AF: 0.463 AC: 2038

ESP6500EA AF: 0.598 AC: 5145

ExAC AF: 0.567 AC: 68818

Asia WGS AF: 0.475 AC: 1655 AN: 3478

EpiCase AF: 0.584

EpiControl AF: 0.580

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.74
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0000066	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.46
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.15
Sift	Benign	0.054	T
Sift4G	Benign	0.21	T
Polyphen		0.27	B
Vest4		0.14
MPC		0.030
ClinPred		0.037	T
GERP RS		0.70
Varity_R		0.13
gMVP		0.54
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1060463; hg19: chr19-16025176; COSMIC: COSV56126742; COSMIC: COSV56126742;