10-122461760-G-T

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.108G>T(p.Gly36Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 1,102,096 control chromosomes in the GnomAD database, including 29,815 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G36G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.23 ( 4202 hom., cov: 32)

Exomes 𝑓: 0.23 ( 25613 hom. )

Consequence

HTRA1
NM_002775.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.25

Publications

32 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=-0.71).

BP6

Variant 10-122461760-G-T is Benign according to our data. Variant chr10-122461760-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.25 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5 link	c.108G>T	p.Gly36Gly	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.108G>T	p.Gly36Gly	synonymous_variant	Exon 1 of 9	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1 link	c.154+3051G>T		intron_variant	Intron 1 of 8			ENSP00000498033.1

Frequencies

GnomAD3 genomes

AF:

0.233

AC:

34326

AN:

147104

Hom.:

4193

Cov.:

show subpopulations

Gnomad AFR

AF:

0.234

Gnomad AMI

AF:

0.235

Gnomad AMR

AF:

0.228

Gnomad ASJ

AF:

0.210

Gnomad EAS

AF:

0.420

Gnomad SAS

AF:

0.312

Gnomad FIN

AF:

0.232

Gnomad MID

AF:

0.170

Gnomad NFE

AF:

0.216

Gnomad OTH

AF:

0.235

GnomAD2 exomes

AF:

0.321

AC:

5727

AN:

17818

AF XY:

0.326

show subpopulations

Gnomad AFR exome

AF:

0.270

Gnomad AMR exome

AF:

0.337

Gnomad ASJ exome

AF:

0.299

Gnomad EAS exome

AF:

0.487

Gnomad FIN exome

AF:

0.301

Gnomad NFE exome

AF:

0.281

Gnomad OTH exome

AF:

0.279

GnomAD4 exome

AF:

0.227

AC:

216639

AN:

954890

Hom.:

25613

Cov.:

AF XY:

0.229

AC XY:

104757

AN XY:

458050

show subpopulations

African (AFR)

AF:

0.245

AC:

4407

AN:

18010

American (AMR)

AF:

0.327

AC:

2242

AN:

6856

Ashkenazi Jewish (ASJ)

AF:

0.238

AC:

2069

AN:

8704

East Asian (EAS)

AF:

0.426

AC:

4451

AN:

10442

South Asian (SAS)

AF:

0.348

AC:

9918

AN:

28486

European-Finnish (FIN)

AF:

0.302

AC:

2825

AN:

9358

Middle Eastern (MID)

AF:

0.228

AC:

491

AN:

2154

European-Non Finnish (NFE)

AF:

0.217

AC:

181910

AN:

837472

Other (OTH)

AF:

0.249

AC:

8326

AN:

33408

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

8472

16944

25416

33888

42360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7856

15712

23568

31424

39280

<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:

0.233

AC:

34371

AN:

147206

Hom.:

4202

Cov.:

AF XY:

0.236

AC XY:

16911

AN XY:

71646

show subpopulations

African (AFR)

AF:

0.234

AC:

9586

AN:

40992

American (AMR)

AF:

0.229

AC:

3404

AN:

14842

Ashkenazi Jewish (ASJ)

AF:

0.210

AC:

714

AN:

3394

East Asian (EAS)

AF:

0.421

AC:

2118

AN:

5034

South Asian (SAS)

AF:

0.313

AC:

1507

AN:

4820

European-Finnish (FIN)

AF:

0.232

AC:

2036

AN:

8772

Middle Eastern (MID)

AF:

0.177

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.216

AC:

14267

AN:

66110

Other (OTH)

AF:

0.232

AC:

476

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1381

2763

4144

5526

6907

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:

0.135

Hom.:

195

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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: 26310622, 18164066, 23478260) -

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

-0.71

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

-1.2

PromoterAI

-0.015

Neutral

(source)

Mutation Taster

=100/0

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