10-93075818-A-G

Position:

• chr10-93075818-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000224356.5(CYP26A1):​c.865-8A>G variant causes a splice region, splice polypyrimidine tract, 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 ENST00000224356.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003761
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.524

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]

ACMG classification

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/exons	MANE	Protein	UniProt
CYP26A1	NM_000783.4	c.865-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000224356.5	NP_000774.2
CYP26A1	NM_057157.2	c.658-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_476498.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP26A1	ENST00000224356.5	c.865-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000783.4	ENSP00000224356	P1
CYP26A1	ENST00000371531.5	c.658-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000360586
CYP26A1	ENST00000623162.1	n.190A>G		non_coding_transcript_exon_variant	1/3	2
CYP26A1	ENST00000624589.3	c.638-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5		ENSP00000485126

Frequencies

GnomAD3 genomes AF: 0.00386 AC: 587 AN: 152106 Hom.: 2 Cov.: 33

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.: 4 AF XY: 0.00394 AC XY: 535 AN XY: 135876

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.: 33 Cov.: 28 AF XY: 0.00596 AC XY: 4321 AN XY: 725260

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.: 2 Cov.: 33 AF XY: 0.00339 AC XY: 252 AN XY: 74436

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.: 0

Bravo AF: 0.00407

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00658

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

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

Other links and lift over

dbSNP: rs41290186; hg19: chr10-94835575;