1-46934183-T-C

Variant names:

• chr1-46934183-T-C
• rs769099199
• NM_000778.4:c.1081A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000778.4(CYP4A11):​c.1081A>G​(p.Ile361Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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. I361L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP4A11 NM_000778.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.936
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11888543).

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.1081A>G	p.Ile361Val	missense	Exon 8 of 12	NP_000769.2	Q02928-1
	CYP4A11	NM_001319155.2		c.985A>G	p.Ile329Val	missense	Exon 8 of 12	NP_001306084.1
	CYP4A11	NM_001363587.2		c.743-52A>G		intron	N/A	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.1081A>G	p.Ile361Val	missense	Exon 8 of 12	ENSP00000311095.4	Q02928-1
	CYP4A11	ENST00000371905.1	TSL:1	c.1081A>G	p.Ile361Val	missense	Exon 8 of 11	ENSP00000360972.1	A0A0C4DFV7
	CYP4A11	ENST00000465874.5	TSL:2	n.609-178A>G		intron	N/A	ENSP00000476368.1	V9GY41

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250860 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461736 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

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

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111906

Other (OTH) AF: 0.00 AC: 0 AN: 60382

⚠️ 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 Cov.: 29

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.94
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.063
Sift	Benign	0.20	T
Sift4G	Benign	0.18	T
Polyphen		0.020	B
Vest4		0.14
MutPred		0.65		Gain of helix (P = 0.2059)
MVP		0.48
MPC		0.057
ClinPred		0.086	T
GERP RS		2.6
Varity_R		0.066
gMVP		0.29
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs769099199; hg19: chr1-47399855;