11-34456207-G-T

Variant names:

• chr11-34456207-G-T
• rs147912187
• NM_001752.4:c.903+5G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_001752.4(CAT):​c.903+5G>T variant causes a splice region, 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_region, intron
• Scores: Splicing: ADA: 0.9983
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.959

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]

ACMG classification

Our verdict: Likely_benign. The variant received -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: {Uncertain_significance=1, Benign=1}.
• BS2: High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAT	NM_001752.4	c.903+5G>T		splice_region_variant, intron_variant	Intron 7 of 12	ENST00000241052.5	NP_001743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAT	ENST00000241052.5	c.903+5G>T		splice_region_variant, intron_variant	Intron 7 of 12	1	NM_001752.4	ENSP00000241052.4
CAT	ENST00000528104.2	n.273+5G>T		splice_region_variant, intron_variant	Intron 2 of 2	2
CAT	ENST00000650153.1	n.*723+5G>T		splice_region_variant, intron_variant	Intron 6 of 8			ENSP00000497751.1

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 288 AN: 152154 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00288 AC: 716 AN: 248270 AF XY: 0.00366

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 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.: 20 Cov.: 29 AF XY: 0.00310 AC XY: 2244 AN XY: 724514

Gnomad4 AFR exome AF: 0.000330 AC: 11 AN: 33352

Gnomad4 AMR exome AF: 0.00125 AC: 56 AN: 44674

Gnomad4 ASJ exome AF: 0.00422 AC: 110 AN: 26090

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39676

Gnomad4 SAS exome AF: 0.0115 AC: 991 AN: 86098

Gnomad4 FIN exome AF: 0.000432 AC: 23 AN: 53188

Gnomad4 NFE exome AF: 0.00229 AC: 2536 AN: 1106586

Gnomad4 Remaining exome AF: 0.00316 AC: 190 AN: 60150

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74460

Gnomad4 AFR AF: 0.000361 AC: 0.000361098 AN: 0.000361098

Gnomad4 AMR AF: 0.00216 AC: 0.00215686 AN: 0.00215686

Gnomad4 ASJ AF: 0.00346 AC: 0.00345821 AN: 0.00345821

Gnomad4 EAS AF: 0.000193 AC: 0.000192753 AN: 0.000192753

Gnomad4 SAS AF: 0.00643 AC: 0.00643154 AN: 0.00643154

Gnomad4 FIN AF: 0.0000944 AC: 0.0000943574 AN: 0.0000943574

Gnomad4 NFE AF: 0.00282 AC: 0.0028222 AN: 0.0028222

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00199 Hom.: 0

Bravo AF: 0.00173

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00474

EpiControl AF: 0.00320

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Acatalasia Uncertain:1

-

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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

Jun 08, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Benign	0.78
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs147912187; hg19: chr11-34477754;