NM_002775.5:c.879C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_002775.5(HTRA1):c.879C>T(p.Thr293Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 1,613,890 control chromosomes in the GnomAD database, including 18 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. T293T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 17 hom. )

Consequence

HTRA1
NM_002775.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.00700

Publications

1 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 10-122506792-C-T is Benign according to our data. Variant chr10-122506792-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 299051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.007 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00278 (423/152196) while in subpopulation NFE AF = 0.00474 (322/67998). AF 95% confidence interval is 0.00431. There are 1 homozygotes in GnomAd4. There are 183 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 17 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5 link	c.879C>T	p.Thr293Thr	synonymous_variant	Exon 4 of 9	ENST00000368984.8	NP_002766.1	Q92743

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HTRA1	ENST00000368984.8 link	c.879C>T	p.Thr293Thr	synonymous_variant	Exon 4 of 9	1	NM_002775.5	ENSP00000357980.3	Q92743
HTRA1	ENST00000648167.1 link	c.561C>T	p.Thr187Thr	synonymous_variant	Exon 4 of 9			ENSP00000498033.1	A0A3B3IU24
HTRA1	ENST00000420892.1 link	c.102C>T	p.Thr34Thr	synonymous_variant	Exon 1 of 6	2		ENSP00000412676.1	H0Y7G9

Frequencies

GnomAD3 genomes

AF:

0.00278

AC:

423

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00473

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00265

AC:

667

AN:

251268

AF XY:

0.00247

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00176

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000511

Gnomad NFE exome

AF:

0.00469

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00449

AC:

6564

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00427

AC XY:

3102

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33480

American (AMR)

AF:

0.00219

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00191

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000162

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000901

AC:

AN:

53252

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00544

AC:

6053

AN:

1111986

Other (OTH)

AF:

0.00459

AC:

277

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

378

756

1135

1513

1891

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

230

460

690

920

1150

<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:

0.00278

AC:

423

AN:

152196

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

183

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.000963

AC:

AN:

41528

American (AMR)

AF:

0.00307

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00474

AC:

322

AN:

67998

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00280

Hom.:

Bravo

AF:

0.00326

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00453

EpiControl

AF:

0.00391

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 20, 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

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HTRA1: BP4, BS2 -

not specified

Benign:1

Feb 19, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Macular degeneration

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

-0.0070

PromoterAI

0.042

Neutral

(source)

Mutation Taster

=99/1

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