rs147912187

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. 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

Verdict is Likely_benign. Variant got -5 ACMG points.

• 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

GnomAD3 exomes AF: 0.00288 AC: 716 AN: 248270 Hom.: 3 AF XY: 0.00366 AC XY: 494 AN XY: 134832

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

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.: 0 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74460

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.: 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

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	24
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

Other links and lift over

dbSNP: rs147912187; hg19: chr11-34477754;