Genetic Variant CYP26A1:c.865-8A>G (chr10-93075818-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_000783.4(CYP26A1):c.865-8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 1,609,298 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0038 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0062 ( 33 hom. )

Consequence

CYP26A1
NM_000783.4 splice_region, intron

Scores

Splicing: ADA: 0.00003761

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.524

Variant links:

Genes affected

CYP26A1 (HGNC:2603): (cytochrome P450 family 26 subfamily A member 1) 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 endoplasmic reticulum protein acts on retinoids, including all-trans-retinoic acid (RA), with both 4-hydroxylation and 18-hydroxylation activities. This enzyme regulates the cellular level of retinoic acid which is involved in regulation of gene expression in both embryonic and adult tissues. Two alternatively spliced transcript variants of this gene, which encode the distinct isoforms, have been reported. [provided by RefSeq, Jul 2008]

CYP26A1 links:

ENSG00000285846 (HGNC:):

ENSG00000285846 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 10-93075818-A-G is Benign according to our data. Variant chr10-93075818-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2640682.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP26A1	NM_000783.4 link	c.865-8A>G		splice_region_variant, intron_variant	Intron 4 of 6	ENST00000224356.5	NP_000774.2	O43174-1
CYP26A1	NM_057157.2 link	c.658-8A>G		splice_region_variant, intron_variant	Intron 4 of 6		NP_476498.1	O43174-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP26A1	ENST00000224356.5 link	c.865-8A>G		splice_region_variant, intron_variant	Intron 4 of 6	1	NM_000783.4	ENSP00000224356.4		O43174-1

Frequencies

GnomAD3 genomes

AF:

0.00386

AC:

587

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00412

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00656

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00386

AC:

971

AN:

251376

Hom.:

AF XY:

0.00394

AC XY:

535

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00281

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00173

Gnomad FIN exome

AF:

0.00213

Gnomad NFE exome

AF:

0.00617

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00616

AC:

8976

AN:

1457074

Hom.:

Cov.:

AF XY:

0.00596

AC XY:

4321

AN XY:

725260

show subpopulations

Gnomad4 AFR exome

AF:

0.000929

Gnomad4 AMR exome

AF:

0.00302

Gnomad4 ASJ exome

AF:

0.00165

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00204

Gnomad4 FIN exome

AF:

0.00223

Gnomad4 NFE exome

AF:

0.00731

Gnomad4 OTH exome

AF:

0.00589

GnomAD4 genome

AF:

0.00385

AC:

586

AN:

152224

Hom.:

Cov.:

AF XY:

0.00339

AC XY:

252

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00104

Gnomad4 AMR

AF:

0.00412

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00656

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00499

Hom.:

Bravo

AF:

0.00407

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00658

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CYP26A1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

2.8

DANN

Benign

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000038

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over