11-34453840-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001752.4(CAT):c.625C>T(p.His209Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,613,330 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (3 hom.)
• Consequence: CAT NM_001752.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.06

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014349788).
• BP6: Variant 11-34453840-C-T is Benign according to our data. Variant chr11-34453840-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 786782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAT	NM_001752.4	c.625C>T	p.His209Tyr	missense_variant	6/13	ENST00000241052.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAT	ENST00000241052.5	c.625C>T	p.His209Tyr	missense_variant	6/13	1	NM_001752.4	P1
CAT	ENST00000650153.1	c.*445C>T		3_prime_UTR_variant, NMD_transcript_variant	5/9
CAT	ENST00000528104.2			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 231 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00184 AC: 463 AN: 251468 Hom.: 0 AF XY: 0.00194 AC XY: 264 AN XY: 135910

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00453

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00205 AC: 2995 AN: 1461008 Hom.: 3 Cov.: 30 AF XY: 0.00203 AC XY: 1477 AN XY: 726882

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00537

Gnomad4 NFE exome AF: 0.00234

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00152 AC: 231 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.00157 AC XY: 117 AN XY: 74486

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00509

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00131

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00222 AC: 270

EpiCase AF: 0.00180

EpiControl AF: 0.00190

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 07, 2023

Variant summary: CAT c.625C>T (p.His209Tyr) results in a conservative amino acid change located in the Catalase core domain (IPR011614) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 1613330 control chromosomes, predominantly at a frequency of 0.0023 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes suggesting a benign role. To our knowledge, no occurrence of c.625C>T in individuals affected with Acatalasia and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	14
Dann	Benign	0.23
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.33	N
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	-2.6	N;N
MutationTaster	Benign	0.53	N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	4.0	N;.
REVEL	Benign	0.27
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.011	B;B
Vest4		0.29
MVP		0.76
MPC		0.15
ClinPred		0.012	T
GERP RS		5.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.088
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs147148220; hg19: chr11-34475387; COSMIC: COSV99074477; COSMIC: COSV99074477;