2-74530427-G-T

Position:

chr2-74530427-G-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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:5

Conservation

PhyloP100: -0.725

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:

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=0.0020277798).

BP6

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

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTRA2	NM_013247.5 linkuse as main transcript	c.421G>T	p.Ala141Ser	missense_variant	1/8	ENST00000258080.8	NP_037379.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTRA2	ENST00000258080.8 linkuse as main transcript	c.421G>T	p.Ala141Ser	missense_variant	1/8	1	NM_013247.5	ENSP00000258080	P1	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

GnomAD3 exomes

AF:

0.0191

AC:

4404

AN:

230376

Hom.:

AF XY:

0.0200

AC XY:

2545

AN XY:

127166

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 SAS exome

AF:

0.0173

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

Gnomad4 AFR exome

AF:

0.00314

Gnomad4 AMR exome

AF:

0.0106

Gnomad4 ASJ exome

AF:

0.0160

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0188

Gnomad4 FIN exome

AF:

0.0271

Gnomad4 NFE exome

AF:

0.0266

Gnomad4 OTH exome

AF:

0.0228

GnomAD4 genome

AF:

0.0171

AC:

2602

AN:

152342

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

1273

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00498

Gnomad4 AMR

AF:

0.0119

Gnomad4 ASJ

AF:

0.0130

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0174

Gnomad4 FIN

AF:

0.0253

Gnomad4 NFE

AF:

0.0261

Gnomad4 OTH

AF:

0.0114

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2018	This variant is associated with the following publications: (PMID: 15961413, 29372317) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Parkinson disease 13, autosomal dominant, susceptibility to

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 15, 2021

- -

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

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;.

MutationTaster

Benign

1.0

N;N

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.33

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

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