dbSNP rs2272599: HTRA1:c.1274+14G>A (chr10-122512079-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002775.5(HTRA1):c.1274+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.615 in 1,560,700 control chromosomes in the GnomAD database, including 297,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.64 ( 31051 hom., cov: 31)

Exomes 𝑓: 0.61 ( 266191 hom. )

Consequence

HTRA1
NM_002775.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.55

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 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 (BayesDel_noAF=-0.86).

BP6

Variant 10-122512079-G-A is Benign according to our data. Variant chr10-122512079-G-A is described in ClinVar as [Benign]. Clinvar id is 299055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-122512079-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5 link	c.1274+14G>A		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+14G>A	intron_variant	Intron 8 of 8	1	NM_002775.5	ENSP00000357980.3	Q92743
HTRA1	ENST00000648167.1 link	c.956+14G>A	intron_variant	Intron 8 of 8			ENSP00000498033.1	A0A3B3IU24
HTRA1	ENST00000420892.1 link	c.497+14G>A	intron_variant	Intron 5 of 5	2		ENSP00000412676.1	H0Y7G9

Frequencies

GnomAD3 genomes

AF:

0.636

AC:

96631

AN:

151932

Hom.:

31039

Cov.:

show subpopulations

Gnomad AFR

AF:

0.701

Gnomad AMI

AF:

0.842

Gnomad AMR

AF:

0.548

Gnomad ASJ

AF:

0.635

Gnomad EAS

AF:

0.610

Gnomad SAS

AF:

0.643

Gnomad FIN

AF:

0.604

Gnomad MID

AF:

0.734

Gnomad NFE

AF:

0.620

Gnomad OTH

AF:

0.636

GnomAD3 exomes

AF:

0.603

AC:

151415

AN:

251216

Hom.:

46563

AF XY:

0.611

AC XY:

82970

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.708

Gnomad AMR exome

AF:

0.436

Gnomad ASJ exome

AF:

0.625

Gnomad EAS exome

AF:

0.627

Gnomad SAS exome

AF:

0.648

Gnomad FIN exome

AF:

0.601

Gnomad NFE exome

AF:

0.620

Gnomad OTH exome

AF:

0.609

GnomAD4 exome

AF:

0.613

AC:

863339

AN:

1408650

Hom.:

266191

Cov.:

AF XY:

0.615

AC XY:

433331

AN XY:

704206

show subpopulations

Gnomad4 AFR exome

AF:

0.704

Gnomad4 AMR exome

AF:

0.448

Gnomad4 ASJ exome

AF:

0.630

Gnomad4 EAS exome

AF:

0.619

Gnomad4 SAS exome

AF:

0.650

Gnomad4 FIN exome

AF:

0.605

Gnomad4 NFE exome

AF:

0.613

Gnomad4 OTH exome

AF:

0.622

GnomAD4 genome

AF:

0.636

AC:

96676

AN:

152050

Hom.:

31051

Cov.:

AF XY:

0.634

AC XY:

47127

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.700

Gnomad4 AMR

AF:

0.547

Gnomad4 ASJ

AF:

0.635

Gnomad4 EAS

AF:

0.609

Gnomad4 SAS

AF:

0.642

Gnomad4 FIN

AF:

0.604

Gnomad4 NFE

AF:

0.620

Gnomad4 OTH

AF:

0.639

Alfa

AF:

0.622

Hom.:

5491

Bravo

AF:

0.631

Asia WGS

AF:

0.610

AC:

2126

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 04, 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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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 12, 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

-0.86

CADD

Benign

0.84

DANN

Benign

0.80

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

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