Genetic Variant CYP26A1:p.Val211Leu (chr10-93074995-G-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000783.4(CYP26A1):c.631G>T(p.Val211Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00346 in 1,613,100 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0030 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 15 hom. )

Consequence

CYP26A1
NM_000783.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 4.76

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008923709).

BP6

Variant 10-93074995-G-T is Benign according to our data. Variant chr10-93074995-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3351143.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP26A1	NM_000783.4 link	c.631G>T	p.Val211Leu	missense_variant	Exon 3 of 7	ENST00000224356.5	NP_000774.2	O43174-1
CYP26A1	NM_057157.2 link	c.424G>T	p.Val142Leu	missense_variant	Exon 3 of 7		NP_476498.1	O43174-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP26A1	ENST00000224356.5 link	c.631G>T	p.Val211Leu	missense_variant	Exon 3 of 7	1	NM_000783.4	ENSP00000224356.4		O43174-1

Frequencies

GnomAD3 genomes

AF:

0.00302

AC:

459

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.114

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00395

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00244

AC:

606

AN:

248640

Hom.:

AF XY:

0.00248

AC XY:

335

AN XY:

135008

show subpopulations

Gnomad AFR exome

AF:

0.000632

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.000300

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00108

Gnomad FIN exome

AF:

0.00208

Gnomad NFE exome

AF:

0.00410

Gnomad OTH exome

AF:

0.00296

GnomAD4 exome

AF:

0.00351

AC:

5121

AN:

1460746

Hom.:

Cov.:

AF XY:

0.00336

AC XY:

2440

AN XY:

726704

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00122

Gnomad4 FIN exome

AF:

0.00227

Gnomad4 NFE exome

AF:

0.00416

Gnomad4 OTH exome

AF:

0.00311

GnomAD4 genome

AF:

0.00301

AC:

459

AN:

152354

Hom.:

Cov.:

AF XY:

0.00295

AC XY:

220

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.00395

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00308

Hom.:

Bravo

AF:

0.00305

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00265

AC:

322

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00376

EpiControl

AF:

0.00373

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CYP26A1-related condition

Benign:1

Aug 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.086

.;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.073

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.0089

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

.;L

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.84

N;N

REVEL

Benign

0.054

Sift

Benign

0.23

T;T

Sift4G

Benign

0.70

T;T

Polyphen

0.0

.;B

Vest4

0.33

MutPred

0.43

.;Gain of disorder (P = 0.1475);

MVP

0.80

MPC

0.21

ClinPred

0.0094

GERP RS

4.1

Varity_R

0.24

gMVP

0.71

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

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