10-93074811-C-G

Position:

• chr10-93074811-C-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The ENST00000224356.5(CYP26A1):​c.447C>G​(p.Leu149=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00569 in 1,608,754 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0057 (30 hom.)
• Consequence: CYP26A1 ENST00000224356.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.50

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 10-93074811-C-G is Benign according to our data. Variant chr10-93074811-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 778469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.5 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP26A1	NM_000783.4	c.447C>G	p.Leu149=	synonymous_variant	3/7	ENST00000224356.5	NP_000774.2
CYP26A1	NM_057157.2	c.240C>G	p.Leu80=	synonymous_variant	3/7		NP_476498.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP26A1	ENST00000224356.5	c.447C>G	p.Leu149=	synonymous_variant	3/7	1	NM_000783.4	ENSP00000224356	P1
CYP26A1	ENST00000371531.5	c.240C>G	p.Leu80=	synonymous_variant	3/7	2		ENSP00000360586
CYP26A1	ENST00000622925.1	n.304C>G		non_coding_transcript_exon_variant	3/3	2
CYP26A1	ENST00000624589.3	c.220C>G	p.Arg74Gly	missense_variant, NMD_transcript_variant	2/6	5		ENSP00000485126

Frequencies

GnomAD3 genomes AF: 0.00536 AC: 816 AN: 152188 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00604

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00516 AC: 1256 AN: 243400 Hom.: 7 AF XY: 0.00530 AC XY: 705 AN XY: 132978

Gnomad AFR exome AF: 0.000896

Gnomad AMR exome AF: 0.00695

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.000720

Gnomad FIN exome AF: 0.000540

Gnomad NFE exome AF: 0.00667

Gnomad OTH exome AF: 0.00908

GnomAD4 exome AF: 0.00572 AC: 8335 AN: 1456448 Hom.: 30 Cov.: 32 AF XY: 0.00571 AC XY: 4141 AN XY: 724756

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00738

Gnomad4 ASJ exome AF: 0.0171

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000684

Gnomad4 FIN exome AF: 0.000743

Gnomad4 NFE exome AF: 0.00625

Gnomad4 OTH exome AF: 0.00646

GnomAD4 genome AF: 0.00535 AC: 815 AN: 152306 Hom.: 10 Cov.: 33 AF XY: 0.00556 AC XY: 414 AN XY: 74472

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00604

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00704 Hom.: 5

Bravo AF: 0.00592

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00916

EpiControl AF: 0.0107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	CYP26A1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.5
DANN	Benign	0.79

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: rs35355587; hg19: chr10-94834568;