rs72470545

Positions:

chr2-74532698-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 4341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74532698-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTRA2	NM_013247.5 linkuse as main transcript	c.1195G>A	p.Gly399Ser	missense_variant	7/8	ENST00000258080.8	NP_037379.1
LOXL3	NM_032603.5 linkuse as main transcript	c.*908C>T		3_prime_UTR_variant	14/14	ENST00000264094.8	NP_115992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTRA2	ENST00000258080.8 linkuse as main transcript	c.1195G>A	p.Gly399Ser	missense_variant	7/8	1	NM_013247.5	ENSP00000258080	P1	O43464-1
LOXL3	ENST00000264094.8 linkuse as main transcript	c.*908C>T		3_prime_UTR_variant	14/14	1	NM_032603.5	ENSP00000264094	P1	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

GnomAD3 exomes

AF:

0.00400

AC:

1007

AN:

251470

Hom.:

AF XY:

0.00478

AC XY:

650

AN XY:

135912

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 SAS exome

AF:

0.0138

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

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.00163

Gnomad4 ASJ exome

AF:

0.00329

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0145

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.00365

Gnomad4 OTH exome

AF:

0.00374

GnomAD4 genome

AF:

0.00265

AC:

404

AN:

152218

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

207

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.00190

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0129

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00377

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00349

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

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	HTRA2: BS1, BS2; LOXL3: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2020	This variant is associated with the following publications: (PMID: 15961413, 18364387, 21701498, 27535533, 26264438, 27884173, 25422467, 25504046) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Parkinson disease 13, autosomal dominant, susceptibility to

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	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. -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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

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

MutationTaster

Benign

1.0

A;A;A;A

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over