10-93074077-C-T

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

3
12
4

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]

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
CYP26A1NM_000783.4 linkc.143C>T p.Thr48Ile missense_variant Exon 1 of 7 ENST00000224356.5 NP_000774.2 O43174-1
CYP26A1NM_057157.2 linkc.-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
CYP26A1ENST00000224356.5 linkc.143C>T p.Thr48Ile missense_variant Exon 1 of 7 1 NM_000783.4 ENSP00000224356.4 O43174-1
CYP26A1ENST00000371531.5 linkc.-18-231C>T intron_variant Intron 1 of 6 2 ENSP00000360586.1 O43174-2
ENSG00000285846ENST00000648258.1 linkn.892-1749C>T intron_variant Intron 1 of 3
CYP26A1ENST00000622925.1 linkn.-1C>T upstream_gene_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0000139
AC:
2
AN:
143908
Hom.:
0
Cov.:
32
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:
17
AN:
1291494
Hom.:
0
Cov.:
28
AF XY:
0.0000141
AC XY:
9
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:
2
AN:
143908
Hom.:
0
Cov.:
32
AF XY:
0.0000143
AC XY:
1
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.:
0

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
T
BayesDel_noAF
Benign
-0.25
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.45
T
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.86
D
M_CAP
Uncertain
0.26
D
MetaRNN
Pathogenic
0.77
D
MetaSVM
Benign
-0.52
T
MutationAssessor
Uncertain
2.3
M
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-3.0
D
REVEL
Uncertain
0.32
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0020
D
Polyphen
0.91
P
Vest4
0.54
MutPred
0.58
Loss of glycosylation at T48 (P = 0.0228);
MVP
0.93
MPC
2.2
ClinPred
0.99
D
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.

Other links and lift over

dbSNP: rs1310797023; hg19: chr10-94833834; API