rs1049331

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002775.5(HTRA1):c.102C>T(p.Ala34Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,116,160 control chromosomes in the GnomAD database, including 30,216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4227 hom., cov: 32)

Exomes 𝑓: 0.23 ( 25989 hom. )

Consequence

HTRA1
NM_002775.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.152

Publications

33 publications found

Variant links:

Genes affected

HTRA1 (HGNC:9476): (HtrA serine peptidase 1) This gene encodes a member of the trypsin family of serine proteases. This protein is a secreted enzyme that is proposed to regulate the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. It has also been suggested to be a regulator of cell growth. Variations in the promoter region of this gene are the cause of susceptibility to age-related macular degeneration type 7. [provided by RefSeq, Jul 2008]

HTRA1 Gene-Disease associations (from GenCC):

CARASIL syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
genetic cerebral small vessel disease
Inheritance: AD Classification: STRONG Submitted by: Franklin by Genoox
HTRA1-related autosomal dominant cerebral small vessel disease
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

HTRA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 10-122461754-C-T is Benign according to our data. Variant chr10-122461754-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.152 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5 link	c.102C>T	p.Ala34Ala	synonymous_variant	Exon 1 of 9	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8 link	c.102C>T	p.Ala34Ala	synonymous_variant	Exon 1 of 9	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1 link	c.154+3045C>T		intron_variant	Intron 1 of 8			ENSP00000498033.1

Frequencies

GnomAD3 genomes

AF:

0.234

AC:

34440

AN:

147136

Hom.:

4216

Cov.:

show subpopulations

Gnomad AFR

AF:

0.236

Gnomad AMI

AF:

0.234

Gnomad AMR

AF:

0.229

Gnomad ASJ

AF:

0.216

Gnomad EAS

AF:

0.422

Gnomad SAS

AF:

0.310

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.216

Gnomad OTH

AF:

0.235

GnomAD2 exomes

AF:

0.323

AC:

6476

AN:

20024

AF XY:

0.328

show subpopulations

Gnomad AFR exome

AF:

0.270

Gnomad AMR exome

AF:

0.332

Gnomad ASJ exome

AF:

0.300

Gnomad EAS exome

AF:

0.522

Gnomad FIN exome

AF:

0.314

Gnomad NFE exome

AF:

0.286

Gnomad OTH exome

AF:

0.289

GnomAD4 exome

AF:

0.226

AC:

219284

AN:

968916

Hom.:

25989

Cov.:

AF XY:

0.228

AC XY:

106332

AN XY:

466516

show subpopulations

African (AFR)

AF:

0.247

AC:

4509

AN:

18232

American (AMR)

AF:

0.311

AC:

2263

AN:

7276

Ashkenazi Jewish (ASJ)

AF:

0.238

AC:

2185

AN:

9190

East Asian (EAS)

AF:

0.423

AC:

4638

AN:

10952

South Asian (SAS)

AF:

0.335

AC:

10472

AN:

31226

European-Finnish (FIN)

AF:

0.291

AC:

2999

AN:

10310

Middle Eastern (MID)

AF:

0.228

AC:

507

AN:

2220

European-Non Finnish (NFE)

AF:

0.217

AC:

183240

AN:

845390

Other (OTH)

AF:

0.248

AC:

8471

AN:

34120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

8272

16544

24815

33087

41359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7862

15724

23586

31448

39310

<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:

0.234

AC:

34488

AN:

147244

Hom.:

4227

Cov.:

AF XY:

0.237

AC XY:

16979

AN XY:

71708

show subpopulations

African (AFR)

AF:

0.236

AC:

9673

AN:

40988

American (AMR)

AF:

0.230

AC:

3415

AN:

14832

Ashkenazi Jewish (ASJ)

AF:

0.216

AC:

731

AN:

3392

East Asian (EAS)

AF:

0.422

AC:

2127

AN:

5036

South Asian (SAS)

AF:

0.311

AC:

1500

AN:

4820

European-Finnish (FIN)

AF:

0.231

AC:

2034

AN:

8802

Middle Eastern (MID)

AF:

0.174

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.216

AC:

14270

AN:

66124

Other (OTH)

AF:

0.232

AC:

476

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1373

2745

4118

5490

6863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

374

748

1122

1496

1870

<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:

0.246

Hom.:

566

Asia WGS

AF:

0.340

AC:

957

AN:

2826

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely 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

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23478260, 18164066, 26310622) -

Macular degeneration

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CARASIL syndrome

Benign:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jun 01, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

9.5

(source)

DANN

Benign

0.96

PhyloP100

0.15

PromoterAI

-0.0015

Neutral

(source)

Mutation Taster

=98/2

polymorphism (auto)

(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