Genetic Variant CYP26A1:p.Thr48Ile (chr10-93074077-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000783.4(CYP26A1):c.143C>T(p.Thr48Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,435,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

CYP26A1
NM_000783.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.52

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP26A1	NM_000783.4 link	c.143C>T	p.Thr48Ile	missense_variant	Exon 1 of 7	ENST00000224356.5	NP_000774.2	O43174-1
CYP26A1	NM_057157.2 link	c.-18-231C>T		intron_variant	Intron 1 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.143C>T	p.Thr48Ile	missense_variant	Exon 1 of 7	1	NM_000783.4	ENSP00000224356.4		O43174-1

Frequencies

GnomAD3 genomes

AF:

0.0000139

AC:

AN:

143908

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000153

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000132

AC:

AN:

1291494

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

639876

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000394

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000160

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000139

AC:

AN:

143908

Hom.:

Cov.:

AF XY:

0.0000143

AC XY:

AN XY:

69906

show subpopulations

Gnomad4 AFR

AF:

0.0000251

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000153

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.143C>T (p.T48I) alteration is located in exon 1 (coding exon 1) of the CYP26A1 gene. This alteration results from a C to T substitution at nucleotide position 143, causing the threonine (T) at amino acid position 48 to be replaced by an isoleucine (I). 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

Pathogenic

0.65

BayesDel_addAF

Benign

-0.0062

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.32

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.91

Vest4

0.54

MutPred

0.58

Loss of glycosylation at T48 (P = 0.0228);

MVP

0.93

MPC

2.2

ClinPred

0.99

GERP RS

3.1

Varity_R

0.60

gMVP

0.72

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