1-47144680-A-T

Position:

• chr1-47144680-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001010969.4(CYP4A22):​c.1028A>T​(p.His343Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP4A22 NM_001010969.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.59

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP4A22	NM_001010969.4	c.1028A>T	p.His343Leu	missense_variant	8/12	ENST00000371891.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4A22	ENST00000371891.8	c.1028A>T	p.His343Leu	missense_variant	8/12	1	NM_001010969.4	P1
CYP4A22-AS1	ENST00000444042.2	n.396+32355T>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250942 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135604

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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

May 18, 2023

The c.1028A>T (p.H343L) alteration is located in exon 8 (coding exon 8) of the CYP4A22 gene. This alteration results from a A to T substitution at nucleotide position 1028, causing the histidine (H) at amino acid position 343 to be replaced by a leucine (L). 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	Benign	0.17
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Benign	0.97
Eigen	Benign	0.049
Eigen_PC	Benign	-0.068
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.48	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.57	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-9.8	D;D;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.64	.;P;.
Vest4		0.61
MutPred		0.55		Loss of disorder (P = 0.039);Loss of disorder (P = 0.039);.;
MVP		0.50
MPC		0.58
ClinPred		1.0	D
GERP RS		1.5
Varity_R		0.93
gMVP		0.62

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: rs745735706; hg19: chr1-47610352;