Genetic Variant CAT:p.His209Asp (chr11-34453840-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001752.4(CAT):c.625C>G(p.His209Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,461,024 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. H209Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CAT
NM_001752.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.06

Publications

12 publications found

Variant links:

Genes affected

CAT (HGNC:1516): (catalase) This gene encodes catalase, a key antioxidant enzyme in the bodies defense against oxidative stress. Catalase is a heme enzyme that is present in the peroxisome of nearly all aerobic cells. Catalase converts the reactive oxygen species hydrogen peroxide to water and oxygen and thereby mitigates the toxic effects of hydrogen peroxide. Oxidative stress is hypothesized to play a role in the development of many chronic or late-onset diseases such as diabetes, asthma, Alzheimer's disease, systemic lupus erythematosus, rheumatoid arthritis, and cancers. Polymorphisms in this gene have been associated with decreases in catalase activity but, to date, acatalasemia is the only disease known to be caused by this gene. [provided by RefSeq, Oct 2009]

CAT Gene-Disease associations (from GenCC):

acatalasia
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

CAT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAT	NM_001752.4 link	c.625C>G	p.His209Asp	missense_variant	Exon 6 of 13	ENST00000241052.5	NP_001743.1	P04040A0A384P5Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAT	ENST00000241052.5 link	c.625C>G	p.His209Asp	missense_variant	Exon 6 of 13	1	NM_001752.4	ENSP00000241052.4	P04040
CAT	ENST00000650153.1 link	n.*445C>G		non_coding_transcript_exon_variant	Exon 5 of 9			ENSP00000497751.1	A0A3B3ITJ0
CAT	ENST00000650153.1 link	n.*445C>G		3_prime_UTR_variant	Exon 5 of 9			ENSP00000497751.1	A0A3B3ITJ0
CAT	ENST00000528104.2 link	n.-6C>G		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251468

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1461024

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726888

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1111240

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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.:

Bravo

AF:

0.0000189

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.84

D;D

Eigen

Benign

0.11

Eigen_PC

Benign

-0.034

FATHMM_MKL

Benign

0.62

LIST_S2

Pathogenic

0.97

.;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

1.9

L;L

PhyloP100

1.1

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.5

D;.

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0010

D;.

Polyphen

0.99

D;D

Vest4

0.72

MutPred

0.81

Loss of catalytic residue at D207 (P = 0.1212);Loss of catalytic residue at D207 (P = 0.1212);

MVP

0.94

MPC

0.65

ClinPred

0.97

GERP RS

5.2

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.75

gMVP

0.95

Mutation Taster

=51/49

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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11-34453840-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over