chr1-47142211-G-A

Position:

• chr1-47142211-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001010969.4(CYP4A22):​c.486G>A​(p.Met162Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP4A22 NM_001010969.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10

Genes affected

CYP4A22 (HGNC:20575): (cytochrome P450 family 4 subfamily A member 22) 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 gene is part of a cluster of cytochrome P450 genes on chromosome 1p33. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

CYP4A22-AS1 (HGNC:43715): (CYP4A22 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13184032).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP4A22	NM_001010969.4	c.486G>A	p.Met162Ile	missense_variant	4/12	ENST00000371891.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4A22	ENST00000371891.8	c.486G>A	p.Met162Ile	missense_variant	4/12	1	NM_001010969.4	P1
CYP4A22-AS1	ENST00000444042.2	n.396+34824C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249348 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134674

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000274 AC: 4 AN: 1460202 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726328

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74444

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2023

The c.486G>A (p.M162I) alteration is located in exon 4 (coding exon 4) of the CYP4A22 gene. This alteration results from a G to A substitution at nucleotide position 486, causing the methionine (M) at amino acid position 162 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.12	.;.;.;T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	D;D;T;T;T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.2	.;.;.;M;.
MutationTaster	Benign	0.80	N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.5	D;.;D;D;.
REVEL	Benign	0.15
Sift	Benign	0.13	T;.;T;T;.
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.13	B;.;.;P;.
Vest4		0.30
MutPred		0.69		Loss of phosphorylation at S165 (P = 0.3283);Loss of phosphorylation at S165 (P = 0.3283);Loss of phosphorylation at S165 (P = 0.3283);Loss of phosphorylation at S165 (P = 0.3283);Loss of phosphorylation at S165 (P = 0.3283);
MVP		0.38
MPC		0.12
ClinPred		0.17	T
GERP RS		1.7
Varity_R		0.20
gMVP		0.53

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: rs189269010; hg19: chr1-47607883;