rs2241027

Variant names:

• chr2-74531539-G-A
• rs2241027
• ENST00000482331.1:n.607G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-74531539-G-A
• chr2-74531539-G-T

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.607G>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 0.0169 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 ENST00000482331.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.253
• Publications: 6 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=-0.63).
• BP6: Variant 2-74531539-G-A is Benign according to our data. Variant chr2-74531539-G-A is described in ClinVar as Benign. ClinVar VariationId 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	c.940-58G>A		intron_variant	Intron 4 of 7	ENST00000258080.8	NP_037379.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 4326 AN: 152144 Hom.: 397 Cov.: 32

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

GnomAD2 exomes AF: 0.0507 AC: 12533 AN: 247414 AF XY: 0.0435

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 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.: 33 AF XY: 0.0151 AC XY: 10937 AN XY: 726434

African (AFR) AF: 0.0282 AC: 942 AN: 33446

American (AMR) AF: 0.143 AC: 6309 AN: 44254

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 68 AN: 26112

East Asian (EAS) AF: 0.265 AC: 10520 AN: 39636

South Asian (SAS) AF: 0.0244 AC: 2105 AN: 86098

European-Finnish (FIN) AF: 0.000281 AC: 15 AN: 53364

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5768

European-Non Finnish (NFE) AF: 0.000942 AC: 1047 AN: 1111372

Other (OTH) AF: 0.0306 AC: 1847 AN: 60340

GnomAD4 genome AF: 0.0285 AC: 4341 AN: 152262 Hom.: 402 Cov.: 32 AF XY: 0.0308 AC XY: 2290 AN XY: 74460

African (AFR) AF: 0.0252 AC: 1046 AN: 41544

American (AMR) AF: 0.0844 AC: 1290 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.316 AC: 1634 AN: 5176

South Asian (SAS) AF: 0.0367 AC: 177 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00168 AC: 114 AN: 68022

Other (OTH) AF: 0.0318 AC: 67 AN: 2108

Alfa AF: 0.0203 Hom.: 405

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

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	10
DANN	Benign	0.67
PhyloP100		0.25
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)		0.10		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: rs2241027; hg19: chr2-74758666; COSMIC: COSV51207867; COSMIC: COSV51207867;