rs17624021

Variant summary

Our verdict is Benign. The variant received -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

2

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]

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=-0.32).
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
HTRA1NM_002775.5 linkc.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
HTRA1ENST00000368984.8 linkc.753C>T p.Ile251Ile synonymous_variant Exon 3 of 9 1 NM_002775.5 ENSP00000357980.3 Q92743
HTRA1ENST00000648167.1 linkc.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.:
33
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
GnomAD2 exomes
AF:
0.0412
AC:
10358
AN:
251438
AF XY:
0.0423
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 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.:
32
AF XY:
0.0508
AC XY:
36901
AN XY:
727082
show subpopulations
Gnomad4 AFR exome
AF:
0.0264
AC:
885
AN:
33468
Gnomad4 AMR exome
AF:
0.0163
AC:
727
AN:
44718
Gnomad4 ASJ exome
AF:
0.0292
AC:
763
AN:
26132
Gnomad4 EAS exome
AF:
0.000403
AC:
16
AN:
39700
Gnomad4 SAS exome
AF:
0.0425
AC:
3665
AN:
86234
Gnomad4 FIN exome
AF:
0.0698
AC:
3729
AN:
53420
Gnomad4 NFE exome
AF:
0.0551
AC:
61259
AN:
1111854
Gnomad4 Remaining exome
AF:
0.0446
AC:
2695
AN:
60368
Heterozygous variant carriers
0
4088
8177
12265
16354
20442
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
2316
4632
6948
9264
11580
<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:
0.0408
AC:
6211
AN:
152186
Hom.:
141
Cov.:
33
AF XY:
0.0415
AC XY:
3086
AN XY:
74398
show subpopulations
Gnomad4 AFR
AF:
0.0272
AC:
0.0271891
AN:
0.0271891
Gnomad4 AMR
AF:
0.0230
AC:
0.0229562
AN:
0.0229562
Gnomad4 ASJ
AF:
0.0302
AC:
0.0302419
AN:
0.0302419
Gnomad4 EAS
AF:
0.000971
AC:
0.000970874
AN:
0.000970874
Gnomad4 SAS
AF:
0.0442
AC:
0.0441542
AN:
0.0441542
Gnomad4 FIN
AF:
0.0743
AC:
0.0742733
AN:
0.0742733
Gnomad4 NFE
AF:
0.0512
AC:
0.0511836
AN:
0.0511836
Gnomad4 OTH
AF:
0.0345
AC:
0.0344991
AN:
0.0344991
Heterozygous variant carriers
0
307
614
920
1227
1534
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
80
160
240
320
400
<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:
0.0435
Hom.:
226
Bravo
AF:
0.0361
Asia WGS
AF:
0.0150
AC:
53
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
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 20, 2017
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
NEI Ophthalmic Genomics Laboratory, National Institutes of Health
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

May 04, 2021
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance:Benign
Review Status:no assertion criteria provided
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
-0.32
CADD
Benign
0.52
DANN
Benign
0.71
Mutation Taster
=98/2
polymorphism (auto)

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.

Other links and lift over

dbSNP: rs17624021; hg19: chr10-124249118; COSMIC: COSV64564913; API