dbSNP rs2672588: HTRA1:c.473-13122T>C (chr10-122475780-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002775.5(HTRA1):c.473-13122T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 152,190 control chromosomes in the GnomAD database, including 5,848 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.27 ( 5848 hom., cov: 34)

Consequence

HTRA1
NM_002775.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.62

Publications

11 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5 link	c.473-13122T>C		intron_variant	Intron 1 of 8	ENST00000368984.8	NP_002766.1	Q92743

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8 link	c.473-13122T>C		intron_variant	Intron 1 of 8	1	NM_002775.5	ENSP00000357980.3		Q92743
HTRA1	ENST00000648167.1 link	c.155-13122T>C		intron_variant	Intron 1 of 8			ENSP00000498033.1		A0A3B3IU24

Frequencies

GnomAD3 genomes

AF:

0.269

AC:

40922

AN:

152072

Hom.:

5850

Cov.:

show subpopulations

Gnomad AFR

AF:

0.341

Gnomad AMI

AF:

0.204

Gnomad AMR

AF:

0.219

Gnomad ASJ

AF:

0.212

Gnomad EAS

AF:

0.0773

Gnomad SAS

AF:

0.0945

Gnomad FIN

AF:

0.232

Gnomad MID

AF:

0.190

Gnomad NFE

AF:

0.273

Gnomad OTH

AF:

0.269

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.269

AC:

40940

AN:

152190

Hom.:

5848

Cov.:

AF XY:

0.262

AC XY:

19526

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.341

AC:

14134

AN:

41488

American (AMR)

AF:

0.219

AC:

3349

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.212

AC:

736

AN:

3470

East Asian (EAS)

AF:

0.0771

AC:

399

AN:

5178

South Asian (SAS)

AF:

0.0948

AC:

458

AN:

4830

European-Finnish (FIN)

AF:

0.232

AC:

2457

AN:

10602

Middle Eastern (MID)

AF:

0.190

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.273

AC:

18599

AN:

68018

Other (OTH)

AF:

0.268

AC:

566

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1581

3161

4742

6322

7903

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

410

820

1230

1640

2050

<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:

0.260

Hom.:

11543

Bravo

AF:

0.272

Asia WGS

AF:

0.0980

AC:

345

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

1.6

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over