rs2241028

Variant names:

• chr2-74531807-G-A
• rs2241028
• ENST00000482331.1:n.875G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000482331.1(HTRA2):​n.875G>A variant causes a non coding transcript exon 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 ENST00000482331.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0200
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• 3-methylglutaconic aciduria type 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 671226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA2	NM_013247.5	c.1046-49G>A		intron_variant	Intron 5 of 7	ENST00000258080.8	NP_037379.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA2	ENST00000258080.8	c.1046-49G>A		intron_variant	Intron 5 of 7	1	NM_013247.5	ENSP00000258080.3

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

GnomAD2 exomes AF: 0.0613 AC: 15377 AN: 250944 AF XY: 0.0639

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 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

African (AFR) AF: 0.0160 AC: 534 AN: 33436

American (AMR) AF: 0.0312 AC: 1393 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 600 AN: 26130

East Asian (EAS) AF: 0.195 AC: 7756 AN: 39688

South Asian (SAS) AF: 0.0846 AC: 7293 AN: 86158

European-Finnish (FIN) AF: 0.0764 AC: 4082 AN: 53396

Middle Eastern (MID) AF: 0.0526 AC: 265 AN: 5038

European-Non Finnish (NFE) AF: 0.0588 AC: 65367 AN: 1111224

Other (OTH) AF: 0.0621 AC: 3742 AN: 60276

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

African (AFR) AF: 0.0184 AC: 764 AN: 41536

American (AMR) AF: 0.0439 AC: 672 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3472

East Asian (EAS) AF: 0.164 AC: 848 AN: 5176

South Asian (SAS) AF: 0.0884 AC: 425 AN: 4810

European-Finnish (FIN) AF: 0.0760 AC: 806 AN: 10600

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0567 AC: 3855 AN: 68012

Other (OTH) AF: 0.0468 AC: 99 AN: 2114

Alfa AF: 0.0540 Hom.: 398

Bravo AF: 0.0469

Asia WGS AF: 0.120 AC: 415 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.8
DANN	Benign	0.46
PhyloP100		-0.020
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2241028; hg19: chr2-74758934; COSMIC: COSV51206506; COSMIC: COSV51206506;