rs17624021

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002775.5(HTRA1):c.753C>T(p.Ile251Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0497 in 1,613,730 control chromosomes in the GnomAD database, including 2,256 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.041 ( 141 hom., cov: 33)

Exomes 𝑓: 0.051 ( 2115 hom. )

Consequence

HTRA1
NM_002775.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 0.232

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 10-122489602-C-T is Benign according to our data. Variant chr10-122489602-C-T is described in ClinVar as [Benign]. Clinvar id is 100572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-122489602-C-T is described in Lovd as [Benign]. Variant chr10-122489602-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.232 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5 link	c.753C>T	p.Ile251Ile	synonymous_variant	Exon 3 of 9	ENST00000368984.8	NP_002766.1	Q92743

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8 link	c.753C>T	p.Ile251Ile	synonymous_variant	Exon 3 of 9	1	NM_002775.5	ENSP00000357980.3		Q92743
HTRA1	ENST00000648167.1 link	c.435C>T	p.Ile145Ile	synonymous_variant	Exon 3 of 9			ENSP00000498033.1		A0A3B3IU24

Frequencies

GnomAD3 genomes

AF:

0.0408

AC:

6208

AN:

152068

Hom.:

141

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0272

Gnomad AMI

AF:

0.0560

Gnomad AMR

AF:

0.0230

Gnomad ASJ

AF:

0.0302

Gnomad EAS

AF:

0.000969

Gnomad SAS

AF:

0.0441

Gnomad FIN

AF:

0.0743

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0512

Gnomad OTH

AF:

0.0349

GnomAD3 exomes

AF:

0.0412

AC:

10358

AN:

251438

Hom.:

276

AF XY:

0.0423

AC XY:

5750

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.0286

Gnomad AMR exome

AF:

0.0151

Gnomad ASJ exome

AF:

0.0314

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0430

Gnomad FIN exome

AF:

0.0705

Gnomad NFE exome

AF:

0.0524

Gnomad OTH exome

AF:

0.0420

GnomAD4 exome

AF:

0.0506

AC:

74011

AN:

1461544

Hom.:

2115

Cov.:

AF XY:

0.0508

AC XY:

36901

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.0264

Gnomad4 AMR exome

AF:

0.0163

Gnomad4 ASJ exome

AF:

0.0292

Gnomad4 EAS exome

AF:

0.000403

Gnomad4 SAS exome

AF:

0.0425

Gnomad4 FIN exome

AF:

0.0698

Gnomad4 NFE exome

AF:

0.0551

Gnomad4 OTH exome

AF:

0.0446

GnomAD4 genome

AF:

0.0408

AC:

6211

AN:

152186

Hom.:

141

Cov.:

AF XY:

0.0415

AC XY:

3086

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0272

Gnomad4 AMR

AF:

0.0230

Gnomad4 ASJ

AF:

0.0302

Gnomad4 EAS

AF:

0.000971

Gnomad4 SAS

AF:

0.0442

Gnomad4 FIN

AF:

0.0743

Gnomad4 NFE

AF:

0.0512

Gnomad4 OTH

AF:

0.0345

Alfa

AF:

0.0451

Hom.:

184

Bravo

AF:

0.0361

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0504

EpiControl

AF:

0.0468

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 20, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

- -

Macular degeneration

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

-0.32

CADD

Benign

0.52

DANN

Benign

0.71

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