19-15914366-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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 Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP4F11	NM_021187.4	c.1336G>A	p.Asp446Asn	missense_variant	Exon 11 of 12	ENST00000402119.9	NP_067010.3
CYP4F11	NM_001128932.2	c.1336G>A	p.Asp446Asn	missense_variant	Exon 12 of 13		NP_001122404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP4F11	ENST00000402119.9	c.1336G>A	p.Asp446Asn	missense_variant	Exon 11 of 12	1	NM_021187.4	ENSP00000384588.2

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

GnomAD3 exomes AF: 0.563 AC: 141549 AN: 251304 Hom.: 40471 AF XY: 0.566 AC XY: 76820 AN XY: 135822

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 SAS exome AF: 0.549

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

Gnomad4 AFR exome AF: 0.458

Gnomad4 AMR exome AF: 0.536

Gnomad4 ASJ exome AF: 0.515

Gnomad4 EAS exome AF: 0.366

Gnomad4 SAS exome AF: 0.548

Gnomad4 FIN exome AF: 0.661

Gnomad4 NFE exome AF: 0.613

Gnomad4 OTH exome AF: 0.582

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

Gnomad4 AFR AF: 0.462

Gnomad4 AMR AF: 0.523

Gnomad4 ASJ AF: 0.516

Gnomad4 EAS AF: 0.395

Gnomad4 SAS AF: 0.552

Gnomad4 FIN AF: 0.667

Gnomad4 NFE AF: 0.605

Gnomad4 OTH AF: 0.526

Alfa AF: 0.579 Hom.: 50817

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 v4.3

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;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.63	.;T;T
MetaRNN	Benign	0.0000066	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.2	D;D;.
REVEL	Benign	0.15
Sift	Benign	0.054	T;T;.
Sift4G	Benign	0.21	T;T;T
Polyphen		0.27	B;B;.
Vest4		0.14
MPC		0.030
ClinPred		0.037	T
GERP RS		0.70
Varity_R		0.13
gMVP		0.54

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