Variant chr2-74531539-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_013247.5(HTRA2):c.940-58G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,612,652 control chromosomes in the GnomAD database, including 2,739 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 402 hom., cov: 32)

Exomes 𝑓: 0.016 ( 2337 hom. )

Consequence

HTRA2
NM_013247.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.253

Variant links:

Genes affected

HTRA2 (HGNC:14348): (HtrA serine peptidase 2) This gene encodes a serine protease. The protein has been localized in the endoplasmic reticulum and interacts with an alternatively spliced form of mitogen-activated protein kinase 14. The protein has also been localized to the mitochondria with release to the cytosol following apoptotic stimulus. The protein is thought to induce apoptosis by binding the apoptosis inhibitory protein baculoviral IAP repeat-containing 4. Nuclear localization of this protein has also been observed. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

HTRA2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 2-74531539-G-A is Benign according to our data. Variant chr2-74531539-G-A is described in ClinVar as [Benign]. Clinvar id is 673578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA2	NM_013247.5 link	c.940-58G>A		intron_variant	Intron 4 of 7	ENST00000258080.8	NP_037379.1	O43464-1A0A384MDW9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA2	ENST00000258080.8 link	c.940-58G>A		intron_variant	Intron 4 of 7	1	NM_013247.5	ENSP00000258080.3		O43464-1

Frequencies

GnomAD3 genomes

AF:

0.0284

AC:

4326

AN:

152144

Hom.:

397

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0841

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.315

Gnomad SAS

AF:

0.0369

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00168

Gnomad OTH

AF:

0.0292

GnomAD3 exomes

AF:

0.0507

AC:

12533

AN:

247414

Hom.:

1434

AF XY:

0.0435

AC XY:

5817

AN XY:

133836

show subpopulations

Gnomad AFR exome

AF:

0.0293

Gnomad AMR exome

AF:

0.147

Gnomad ASJ exome

AF:

0.00319

Gnomad EAS exome

AF:

0.329

Gnomad SAS exome

AF:

0.0249

Gnomad FIN exome

AF:

0.000279

Gnomad NFE exome

AF:

0.00176

Gnomad OTH exome

AF:

0.0327

GnomAD4 exome

AF:

0.0157

AC:

22931

AN:

1460390

Hom.:

2337

Cov.:

AF XY:

0.0151

AC XY:

10937

AN XY:

726434

show subpopulations

Gnomad4 AFR exome

AF:

0.0282

Gnomad4 AMR exome

AF:

0.143

Gnomad4 ASJ exome

AF:

0.00260

Gnomad4 EAS exome

AF:

0.265

Gnomad4 SAS exome

AF:

0.0244

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.000942

Gnomad4 OTH exome

AF:

0.0306

GnomAD4 genome

AF:

0.0285

AC:

4341

AN:

152262

Hom.:

402

Cov.:

AF XY:

0.0308

AC XY:

2290

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0252

Gnomad4 AMR

AF:

0.0844

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.316

Gnomad4 SAS

AF:

0.0367

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00168

Gnomad4 OTH

AF:

0.0318

Alfa

AF:

0.0116

Hom.:

138

Bravo

AF:

0.0390

Asia WGS

AF:

0.163

AC:

564

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.67

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

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