11-34456207-G-T

Position:

chr11-34456207-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_001752.4(CAT):c.903+5G>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,607,840 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 20 hom. )

Consequence

CAT
NM_001752.4 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.9983

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.959

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BP6

Variant 11-34456207-G-T is Benign according to our data. Variant chr11-34456207-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 773245.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAT	NM_001752.4 linkuse as main transcript	c.903+5G>T		splice_donor_5th_base_variant, intron_variant		ENST00000241052.5	NP_001743.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris
CAT	ENST00000241052.5 linkuse as main transcript	c.903+5G>T	splice_donor_5th_base_variant, intron_variant	1	NM_001752.4	ENSP00000241052	P1
CAT	ENST00000650153.1 linkuse as main transcript	c.*723+5G>T	splice_donor_5th_base_variant, intron_variant, NMD_transcript_variant			ENSP00000497751
CAT	ENST00000528104.2 linkuse as main transcript	n.273+5G>T	splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant	2

Frequencies

GnomAD3 genomes

AF:

0.00189

AC:

288

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00643

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00284

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00288

AC:

716

AN:

248270

Hom.:

AF XY:

0.00366

AC XY:

494

AN XY:

134832

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00361

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0107

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00252

Gnomad OTH exome

AF:

0.00315

GnomAD4 exome

AF:

0.00272

AC:

3963

AN:

1455570

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

2244

AN XY:

724514

show subpopulations

Gnomad4 AFR exome

AF:

0.000330

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.00422

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0115

Gnomad4 FIN exome

AF:

0.000432

Gnomad4 NFE exome

AF:

0.00229

Gnomad4 OTH exome

AF:

0.00316

GnomAD4 genome

AF:

0.00188

AC:

286

AN:

152270

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00643

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.00282

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00227

Hom.:

Bravo

AF:

0.00173

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00474

EpiControl

AF:

0.00320

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Acatalasia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The heterozygous c.903+5G>T variant in CAT has been identified in 2 Hungarian relatives from 1 family with hypocatalasaemia (PMID: 11197178), and has been identified in >1% of South Asian chromosomes and 1 homozygote by ExAC (http://gnomad.broadinstitute.org/). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In summary, the clinical significance of this variant is uncertain. -

CAT-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2022

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). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

DANN

Benign

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.86

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.23

Position offset: -5

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