Genetic Variant NM_000783.4:c.436C>G (chr10-93074800-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000783.4(CYP26A1):c.436C>G(p.Arg146Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R146S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CYP26A1
NM_000783.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.19

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.786

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000783.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP26A1	NM_000783.4	MANE Select	c.436C>G	p.Arg146Gly	missense	Exon 3 of 7	NP_000774.2
	CYP26A1	NM_057157.2		c.229C>G	p.Arg77Gly	missense	Exon 3 of 7	NP_476498.1	O43174-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP26A1	ENST00000224356.5	TSL:1 MANE Select	c.436C>G	p.Arg146Gly	missense	Exon 3 of 7	ENSP00000224356.4	O43174-1
CYP26A1	ENST00000371531.5	TSL:2	c.229C>G	p.Arg77Gly	missense	Exon 3 of 7	ENSP00000360586.1	O43174-2
CYP26A1	ENST00000622925.1	TSL:2	n.293C>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454382

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723768

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111504

Other (OTH)

AF:

0.00

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Benign

-0.092

Eigen_PC

Benign

0.060

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

M_CAP

Benign

0.041

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.1

PhyloP100

3.2

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.4

REVEL

Uncertain

0.41

Sift

Uncertain

0.014

Sift4G

Benign

0.23

Polyphen

0.032

Vest4

0.86

MutPred

0.62

Loss of MoRF binding (P = 0.0213)

MVP

0.81

MPC

2.5

ClinPred

0.99

GERP RS

5.0

Varity_R

0.83

gMVP

0.78

Mutation Taster

=17/83

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over