rs72470545

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.1195G>A(p.Gly399Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00383 in 1,613,838 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 28 hom. )

Consequence

HTRA2
NM_013247.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.92

Publications

81 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 links:

LOXL3 (HGNC:13869): (lysyl oxidase like 3) This gene encodes a lysyl oxidase, which likely functions as an amine oxidase and plays a role in the formation of crosslinks in collagens and elastin. Deletion of the related gene in mouse causes neonatal mortality with cleft palate, spine deformity, and defects in collagen organization. A mutation in this gene was found in a family with Stickler syndrome. [provided by RefSeq, Sep 2016]

LOXL3 Gene-Disease associations (from GenCC):

myopia 28, autosomal recessive
Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Stickler syndrome
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp
autosomal recessive Stickler syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOXL3 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=0.009953827).

BP6

Variant 2-74532698-G-A is Benign according to our data. Variant chr2-74532698-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 4341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00265 (404/152218) while in subpopulation SAS AF = 0.0129 (62/4820). AF 95% confidence interval is 0.0103. There are 1 homozygotes in GnomAd4. There are 207 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA2	NM_013247.5 link	c.1195G>A	p.Gly399Ser	missense_variant	Exon 7 of 8	ENST00000258080.8	NP_037379.1	O43464-1A0A384MDW9
LOXL3	NM_032603.5 link	c.*908C>T		3_prime_UTR_variant	Exon 14 of 14	ENST00000264094.8	NP_115992.1	P58215-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA2	ENST00000258080.8 link	c.1195G>A	p.Gly399Ser	missense_variant	Exon 7 of 8	1	NM_013247.5	ENSP00000258080.3		O43464-1
LOXL3	ENST00000264094.8 link	c.*908C>T		3_prime_UTR_variant	Exon 14 of 14	1	NM_032603.5	ENSP00000264094.3		P58215-1

Frequencies

GnomAD3 genomes

AF:

0.00266

AC:

404

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0126

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00376

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00400

AC:

1007

AN:

251470

AF XY:

0.00478

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00357

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00411

Gnomad OTH exome

AF:

0.00309

GnomAD4 exome

AF:

0.00395

AC:

5774

AN:

1461620

Hom.:

Cov.:

AF XY:

0.00438

AC XY:

3182

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.000717

AC:

AN:

33472

American (AMR)

AF:

0.00163

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00329

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0145

AC:

1249

AN:

86242

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00801

AC:

AN:

5618

European-Non Finnish (NFE)

AF:

0.00365

AC:

4062

AN:

1111952

Other (OTH)

AF:

0.00374

AC:

226

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

327

654

981

1308

1635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

162

324

486

648

810

<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:

0.00265

AC:

404

AN:

152218

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

207

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41536

American (AMR)

AF:

0.00190

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.0129

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00377

AC:

256

AN:

67994

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00353

Hom.:

Bravo

AF:

0.00274

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00437

AC:

531

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.00425

EpiControl

AF:

0.00445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HTRA2: BS1, BS2; LOXL3: BS1, BS2 -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 05, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15961413, 18364387, 21701498, 27535533, 26264438, 27884173, 25422467, 25504046) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Parkinson disease 13, autosomal dominant, susceptibility to

Uncertain:1Benign:2

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Gly399Ser variant in HTRA2 has been identified in 4 individuals with Parkinson disease and individuals without Parkinson disease (PMID: 15961413, 18364387, 25422467), but has also been identified in >1% of South Asian chromosomes and 4 homozoygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for Parkinson disease. -

Jul 01, 2008

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.010

MetaSVM

Uncertain

0.54

MutationAssessor

Uncertain

2.3

PhyloP100

4.9

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.79

Sift

Uncertain

0.020

Sift4G

Uncertain

0.021

Polyphen

0.99

Vest4

0.30

MVP

0.94

MPC

1.4

ClinPred

0.028

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.77

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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