10-122461711-C-T

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.59C>T(p.Ala20Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00962 in 1,297,084 control chromosomes in the GnomAD database, including 544 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 85 hom., cov: 32)

Exomes 𝑓: 0.0094 ( 459 hom. )

Consequence

HTRA1
NM_002775.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.298

Publications

14 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 (MetaRNN=0.0015049279).

BP6

Variant 10-122461711-C-T is Benign according to our data. Variant chr10-122461711-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 299044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5 link	c.59C>T	p.Ala20Val	missense_variant	Exon 1 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.59C>T	p.Ala20Val	missense_variant	Exon 1 of 9	1	NM_002775.5	ENSP00000357980.3		Q92743
HTRA1	ENST00000648167.1 link	c.154+3002C>T		intron_variant	Intron 1 of 8			ENSP00000498033.1		A0A3B3IU24

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1739

AN:

147886

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00248

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0165

Gnomad ASJ

AF:

0.000587

Gnomad EAS

AF:

0.161

Gnomad SAS

AF:

0.0395

Gnomad FIN

AF:

0.00445

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00464

Gnomad OTH

AF:

0.0128

GnomAD2 exomes

AF:

0.0212

AC:

1513

AN:

71438

AF XY:

0.0210

show subpopulations

Gnomad AFR exome

AF:

0.00120

Gnomad AMR exome

AF:

0.0305

Gnomad ASJ exome

AF:

0.00229

Gnomad EAS exome

AF:

0.154

Gnomad FIN exome

AF:

0.00292

Gnomad NFE exome

AF:

0.00406

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.00935

AC:

10745

AN:

1149088

Hom.:

459

Cov.:

AF XY:

0.0102

AC XY:

5779

AN XY:

565652

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

21710

American (AMR)

AF:

0.0281

AC:

594

AN:

21124

Ashkenazi Jewish (ASJ)

AF:

0.00241

AC:

AN:

16190

East Asian (EAS)

AF:

0.196

AC:

3003

AN:

15344

South Asian (SAS)

AF:

0.0354

AC:

2377

AN:

67198

European-Finnish (FIN)

AF:

0.00328

AC:

AN:

21006

Middle Eastern (MID)

AF:

0.00234

AC:

AN:

2994

European-Non Finnish (NFE)

AF:

0.00416

AC:

3915

AN:

940520

Other (OTH)

AF:

0.0165

AC:

709

AN:

43002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

459

917

1376

1834

2293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0117

AC:

1737

AN:

147996

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

936

AN XY:

72122

show subpopulations

African (AFR)

AF:

0.00257

AC:

106

AN:

41168

American (AMR)

AF:

0.0166

AC:

247

AN:

14902

Ashkenazi Jewish (ASJ)

AF:

0.000587

AC:

AN:

3406

East Asian (EAS)

AF:

0.161

AC:

819

AN:

5094

South Asian (SAS)

AF:

0.0392

AC:

189

AN:

4826

European-Finnish (FIN)

AF:

0.00445

AC:

AN:

8990

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00464

AC:

308

AN:

66352

Other (OTH)

AF:

0.0126

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

157

235

314

392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00648

Hom.:

Bravo

AF:

0.0125

ExAC

AF:

0.0165

AC:

448

Asia WGS

AF:

0.0670

AC:

203

AN:

3010

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

May 04, 2021

GeneDx

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

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Macular degeneration

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely 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

- -

CARASIL syndrome

Benign:1

May 31, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.9

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.086

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

PhyloP100

0.30

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.58

REVEL

Benign

0.16

Sift

Benign

0.63

Sift4G

Benign

0.21

Polyphen

0.0010

Vest4

0.045

MPC

0.51

ClinPred

0.0038

GERP RS

0.42

PromoterAI

-0.0072

Neutral

(source)

Varity_R

0.062

gMVP

0.48

Mutation Taster

=100/0

polymorphism (auto)

(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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10-122461711-C-T

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