rs1126742

Variant names:

• chr1-46932824-A-G
• rs1126742
• NM_000778.4:c.1301T>C
• CYP4A11 p.Phe434Ser

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 89 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000778.4. 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
	CYP4A11	NM_000778.4	MANE Select	c.1301T>C	p.Phe434Ser	missense	Exon 11 of 12	NP_000769.2	Q02928-1
	CYP4A11	NM_001319155.2		c.1205T>C	p.Phe402Ser	missense	Exon 11 of 12	NP_001306084.1
	CYP4A11	NM_001363587.2		c.1007T>C	p.Phe336Ser	missense	Exon 9 of 10	NP_001350516.1	V9GZ77

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4A11	ENST00000310638.9	TSL:1 MANE Select	c.1301T>C	p.Phe434Ser	missense	Exon 11 of 12	ENSP00000311095.4	Q02928-1
	CYP4A11	ENST00000371905.1	TSL:1	c.1301T>C	p.Phe434Ser	missense	Exon 11 of 11	ENSP00000360972.1	A0A0C4DFV7
	CYP4A11	ENST00000465874.5	TSL:2	n.*99T>C		non_coding_transcript_exon	Exon 8 of 8	ENSP00000476368.1	V9GY41

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

GnomAD2 exomes AF: 0.173 AC: 43502 AN: 251044 AF XY: 0.178

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.322 AC: 10714 AN: 33226

American (AMR) AF: 0.146 AC: 6510 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 3236 AN: 26060

East Asian (EAS) AF: 0.222 AC: 8800 AN: 39586

South Asian (SAS) AF: 0.286 AC: 24529 AN: 85864

European-Finnish (FIN) AF: 0.134 AC: 7140 AN: 53376

Middle Eastern (MID) AF: 0.183 AC: 1051 AN: 5752

European-Non Finnish (NFE) AF: 0.135 AC: 149546 AN: 1105692

Other (OTH) AF: 0.162 AC: 9717 AN: 60082

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.312 AC: 12921 AN: 41442

American (AMR) AF: 0.159 AC: 2435 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 447 AN: 3470

East Asian (EAS) AF: 0.226 AC: 1169 AN: 5166

South Asian (SAS) AF: 0.284 AC: 1365 AN: 4808

European-Finnish (FIN) AF: 0.135 AC: 1431 AN: 10590

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9270 AN: 67972

Other (OTH) AF: 0.177 AC: 373 AN: 2112

Alfa AF: 0.149 Hom.: 3339

Bravo AF: 0.199

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 v4.9

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
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.73	N
PhyloP100		0.076
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.040
Sift	Benign	0.68	T
Sift4G	Benign	0.60	T
Varity_R		0.059
gMVP		0.57
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

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