rs2241028

Positions:

• chr2-74531807-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_013247.5(HTRA2):​c.1046-49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0612 in 1,612,272 control chromosomes in the GnomAD database, including 3,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.051 (267 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3413 hom.)
• Consequence: HTRA2 NM_013247.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0200

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-74531807-G-A is Benign according to our data. Variant chr2-74531807-G-A is described in ClinVar as [Benign]. Clinvar id is 671226.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTRA2	NM_013247.5	c.1046-49G>A		intron_variant		ENST00000258080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTRA2	ENST00000258080.8	c.1046-49G>A		intron_variant		1	NM_013247.5	P1

Frequencies

GnomAD3 genomes AF: 0.0507 AC: 7710 AN: 152112 Hom.: 267 Cov.: 32

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0440

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.0883

Gnomad FIN AF: 0.0760

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0567

Gnomad OTH AF: 0.0473

GnomAD3 exomes AF: 0.0613 AC: 15377 AN: 250944 Hom.: 655 AF XY: 0.0639 AC XY: 8667 AN XY: 135632

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.0286

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.165

Gnomad SAS exome AF: 0.0834

Gnomad FIN exome AF: 0.0759

Gnomad NFE exome AF: 0.0561

Gnomad OTH exome AF: 0.0531

GnomAD4 exome AF: 0.0623 AC: 91032 AN: 1460042 Hom.: 3413 Cov.: 32 AF XY: 0.0633 AC XY: 45994 AN XY: 726370

Gnomad4 AFR exome AF: 0.0160

Gnomad4 AMR exome AF: 0.0312

Gnomad4 ASJ exome AF: 0.0230

Gnomad4 EAS exome AF: 0.195

Gnomad4 SAS exome AF: 0.0846

Gnomad4 FIN exome AF: 0.0764

Gnomad4 NFE exome AF: 0.0588

Gnomad4 OTH exome AF: 0.0621

GnomAD4 genome AF: 0.0506 AC: 7707 AN: 152230 Hom.: 267 Cov.: 32 AF XY: 0.0528 AC XY: 3932 AN XY: 74434

Gnomad4 AFR AF: 0.0184

Gnomad4 AMR AF: 0.0439

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.164

Gnomad4 SAS AF: 0.0884

Gnomad4 FIN AF: 0.0760

Gnomad4 NFE AF: 0.0567

Gnomad4 OTH AF: 0.0468

Alfa AF: 0.0552 Hom.: 333

Bravo AF: 0.0469

Asia WGS AF: 0.120 AC: 415 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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	-0.87
CADD	Benign	7.8
DANN	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2241028; hg19: chr2-74758934; COSMIC: COSV51206506; COSMIC: COSV51206506;