2-74530427-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_013247.5(HTRA2):c.421G>T(p.Ala141Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0234 in 1,603,176 control chromosomes in the GnomAD database, including 485 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A141A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.017 ( 25 hom., cov: 33)

Exomes 𝑓: 0.024 ( 460 hom. )

Consequence

HTRA2
NM_013247.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:6

Conservation

PhyloP100: -0.725

Publications

42 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: G2P, ClinGen, 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 (MetaRNN=0.0020277798).

BP6

Variant 2-74530427-G-T is Benign according to our data. Variant chr2-74530427-G-T is described in ClinVar as Benign. ClinVar VariationId is 4342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0171 (2602/152342) while in subpopulation NFE AF = 0.0261 (1777/68030). AF 95% confidence interval is 0.0251. There are 25 homozygotes in GnomAd4. There are 1273 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA2	NM_013247.5 link	c.421G>T	p.Ala141Ser	missense_variant	Exon 1 of 8	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.421G>T	p.Ala141Ser	missense_variant	Exon 1 of 8	1	NM_013247.5	ENSP00000258080.3		O43464-1

Frequencies

GnomAD3 genomes

AF:

0.0171

AC:

2600

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00499

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0119

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.0253

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0261

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0191

AC:

4404

AN:

230376

AF XY:

0.0200

show subpopulations

Gnomad AFR exome

AF:

0.00377

Gnomad AMR exome

AF:

0.0102

Gnomad ASJ exome

AF:

0.0151

Gnomad EAS exome

AF:

0.0000574

Gnomad FIN exome

AF:

0.0283

Gnomad NFE exome

AF:

0.0266

Gnomad OTH exome

AF:

0.0204

GnomAD4 exome

AF:

0.0241

AC:

34943

AN:

1450834

Hom.:

460

Cov.:

AF XY:

0.0240

AC XY:

17360

AN XY:

721836

show subpopulations

African (AFR)

AF:

0.00314

AC:

105

AN:

33404

American (AMR)

AF:

0.0106

AC:

473

AN:

44442

Ashkenazi Jewish (ASJ)

AF:

0.0160

AC:

416

AN:

26064

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39568

South Asian (SAS)

AF:

0.0188

AC:

1614

AN:

85974

European-Finnish (FIN)

AF:

0.0271

AC:

1214

AN:

44840

Middle Eastern (MID)

AF:

0.0354

AC:

204

AN:

5764

European-Non Finnish (NFE)

AF:

0.0266

AC:

29543

AN:

1110608

Other (OTH)

AF:

0.0228

AC:

1372

AN:

60170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2042

4084

6126

8168

10210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1070

2140

3210

4280

5350

<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:

0.0171

AC:

2602

AN:

152342

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

1273

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00498

AC:

207

AN:

41588

American (AMR)

AF:

0.0119

AC:

182

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.0174

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0253

AC:

269

AN:

10616

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0261

AC:

1777

AN:

68030

Other (OTH)

AF:

0.0114

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

136

271

407

542

678

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0159

Hom.:

Bravo

AF:

0.0161

TwinsUK

AF:

0.0283

AC:

105

ALSPAC

AF:

0.0231

AC:

ESP6500AA

AF:

0.00398

AC:

ESP6500EA

AF:

0.0255

AC:

214

ExAC

AF:

0.0196

AC:

2363

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15961413, 29372317) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Parkinson disease 13, autosomal dominant, susceptibility to

Uncertain:1Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 01, 2008

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Parkinson disease 13, autosomal dominant, susceptibility to;C4310650:3-methylglutaconic aciduria type 8

Benign:2

Nov 18, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Oct 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.82

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.052

T;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.56

T;T;T

MetaRNN

Benign

0.0020

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.34

N;N;.

PhyloP100

-0.72

PrimateAI

Benign

0.46

PROVEAN

Benign

1.5

N;N;N

REVEL

Benign

0.015

Sift

Benign

0.81

T;T;T

Sift4G

Benign

0.91

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.019

MPC

0.82

ClinPred

0.00062

GERP RS

-1.0

PromoterAI

0.065

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.33

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over