rs1126742

Positions:

• chr1-46932824-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000778.4(CYP4A11):​c.1301T>C​(p.Phe434Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,606,278 control chromosomes in the GnomAD database, including 22,684 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.19 (3330 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19354 hom.)
• Consequence: CYP4A11 NM_000778.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0760

Genes affected

CYP4A11 (HGNC:2642): (cytochrome P450 family 4 subfamily A member 11) 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 hydroxylates medium-chain fatty acids such as laurate and myristate. Multiple transcript variants have been found for this gene. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030956566).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP4A11	NM_000778.4	c.1301T>C	p.Phe434Ser	missense_variant	11/12	ENST00000310638.9	NP_000769.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP4A11	ENST00000310638.9	c.1301T>C	p.Phe434Ser	missense_variant	11/12	1	NM_000778.4	ENSP00000311095	P1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29615 AN: 151946 Hom.: 3324 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.178

GnomAD3 exomes AF: 0.173 AC: 43502 AN: 251044 Hom.: 4392 AF XY: 0.178 AC XY: 24122 AN XY: 135668

Gnomad AFR exome AF: 0.321

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.240

Gnomad SAS exome AF: 0.286

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.152 AC: 221243 AN: 1454214 Hom.: 19354 Cov.: 33 AF XY: 0.155 AC XY: 112271 AN XY: 723086

Gnomad4 AFR exome AF: 0.322

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.286

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.162

GnomAD4 genome AF: 0.195 AC: 29643 AN: 152064 Hom.: 3330 Cov.: 32 AF XY: 0.196 AC XY: 14591 AN XY: 74346

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.159

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.226

Gnomad4 SAS AF: 0.284

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.177

Alfa AF: 0.157 Hom.: 1041

Bravo AF: 0.199

ESP6500AA AF: 0.289 AC: 1273

ESP6500EA AF: 0.130 AC: 1115

ExAC AF: 0.176 AC: 21430

Asia WGS AF: 0.239 AC: 830 AN: 3478

EpiCase AF: 0.141

EpiControl AF: 0.137

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	2.1
DANN	Benign	0.73
DEOGEN2	Benign	0.065	T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0078	N
LIST_S2	Benign	0.16	T;T;T;T
MetaRNN	Benign	0.0031	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.73	N;.;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.9	N;N;.;N
REVEL	Benign	0.040
Sift	Benign	0.68	T;T;.;T
Sift4G	Benign	0.60	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.022
MPC		0.098
ClinPred		0.00030	T
GERP RS		0.32
Varity_R		0.059
gMVP		0.57

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: rs1126742; hg19: chr1-47398496; COSMIC: COSV60222115; COSMIC: COSV60222115;