NM_002775.5:c.1274+8G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002775.5(HTRA1):c.1274+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,586,922 control chromosomes in the GnomAD database, including 793,253 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 1.0 ( 76039 hom., cov: 31)

Exomes 𝑓: 1.0 ( 717214 hom. )

Consequence

HTRA1
NM_002775.5 splice_region, intron

Scores

Splicing: ADA: 0.0001040

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.10

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 10-122512073-G-A is Benign according to our data. Variant chr10-122512073-G-A is described in ClinVar as [Benign]. Clinvar id is 299054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5 link	c.1274+8G>A		splice_region_variant, intron_variant	Intron 8 of 8	ENST00000368984.8	NP_002766.1	Q92743

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HTRA1	ENST00000368984.8 link	c.1274+8G>A	splice_region_variant, intron_variant	Intron 8 of 8	1	NM_002775.5	ENSP00000357980.3	Q92743
HTRA1	ENST00000648167.1 link	c.956+8G>A	splice_region_variant, intron_variant	Intron 8 of 8			ENSP00000498033.1	A0A3B3IU24
HTRA1	ENST00000420892.1 link	c.497+8G>A	splice_region_variant, intron_variant	Intron 5 of 5	2		ENSP00000412676.1	H0Y7G9

Frequencies

GnomAD3 genomes

AF:

0.999

AC:

152048

AN:

152132

Hom.:

75982

Cov.:

show subpopulations

Gnomad AFR

AF:

0.998

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

1.00

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.999

GnomAD2 exomes

AF:

1.00

AC:

251368

AN:

251408

AF XY:

1.00

show subpopulations

Gnomad AFR exome

AF:

0.998

Gnomad AMR exome

AF:

1.00

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

1.00

GnomAD4 exome

AF:

1.00

AC:

1434548

AN:

1434670

Hom.:

717214

Cov.:

AF XY:

1.00

AC XY:

715579

AN XY:

715634

show subpopulations

African (AFR)

AF:

0.998

AC:

32889

AN:

32960

American (AMR)

AF:

1.00

AC:

44673

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

25982

AN:

25982

East Asian (EAS)

AF:

1.00

AC:

39548

AN:

39548

South Asian (SAS)

AF:

1.00

AC:

85694

AN:

85696

European-Finnish (FIN)

AF:

1.00

AC:

53372

AN:

53372

Middle Eastern (MID)

AF:

0.999

AC:

5665

AN:

5670

European-Non Finnish (NFE)

AF:

1.00

AC:

1087281

AN:

1087294

Other (OTH)

AF:

1.00

AC:

59444

AN:

59462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.999

AC:

152165

AN:

152252

Hom.:

76039

Cov.:

AF XY:

1.00

AC XY:

74405

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.998

AC:

41478

AN:

41558

American (AMR)

AF:

1.00

AC:

15294

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3470

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5158

AN:

5158

South Asian (SAS)

AF:

1.00

AC:

4806

AN:

4806

European-Finnish (FIN)

AF:

1.00

AC:

10608

AN:

10608

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68031

AN:

68032

Other (OTH)

AF:

0.999

AC:

2114

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

1.00

Hom.:

32783

Bravo

AF:

0.999

Asia WGS

AF:

0.999

AC:

3476

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

May 03, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 12, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CARASIL syndrome

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Macular degeneration

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.80

(source)

DANN

Benign

0.77

PhyloP100

-1.1

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00010

dbscSNV1_RF

Benign

0.076

SpliceAI score (max)

0.040

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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NM_002775.5:c.1274+8G>A

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