dbSNP rs2241028: HTRA2:c.1046-49G>A (chr2-74531807-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0200

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

3-methylglutaconic aciduria type 8
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)

HTRA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013247.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HTRA2	NM_013247.5	MANE Select	c.1046-49G>A	intron	N/A	NP_037379.1	O43464-1
HTRA2	NM_001321727.1		c.1076-49G>A	intron	N/A	NP_001308656.1	O43464-3
HTRA2	NM_001321728.1		c.1046-49G>A	intron	N/A	NP_001308657.1	A0A8Q3SIX7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HTRA2	ENST00000258080.8	TSL:1 MANE Select	c.1046-49G>A	intron	N/A	ENSP00000258080.3	O43464-1
HTRA2	ENST00000437202.2	TSL:1	c.1076-49G>A	intron	N/A	ENSP00000399166.2	O43464-3
HTRA2	ENST00000352222.7	TSL:1	c.851-49G>A	intron	N/A	ENSP00000312893.3	O43464-2

Frequencies

GnomAD3 genomes

AF:

0.0507

AC:

7710

AN:

152112

Hom.:

267

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0633

AC XY:

45994

AN XY:

726370

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

5058

10116

15175

20233

25291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2516

5032

7548

10064

12580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0506

AC:

7707

AN:

152230

Hom.:

267

Cov.:

AF XY:

0.0528

AC XY:

3932

AN XY:

74434

show subpopulations

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:

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0567

AC:

3855

AN:

68012

Other (OTH)

AF:

0.0468

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

367

733

1100

1466

1833

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0540

Hom.:

398

Bravo

AF:

0.0469

Asia WGS

AF:

0.120

AC:

415

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

7.8

(source)

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)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over