chr10-122514155-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.1275-36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,605,236 control chromosomes in the GnomAD database, including 33,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.18 ( 2928 hom., cov: 31)

Exomes 𝑓: 0.20 ( 30930 hom. )

Consequence

HTRA1
NM_002775.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.246

Publications

15 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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 10-122514155-C-T is Benign according to our data. Variant chr10-122514155-C-T is described in ClinVar as Benign. ClinVar VariationId is 1259856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5 link	c.1275-36C>T		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.1275-36C>T	intron_variant	Intron 8 of 8	1	NM_002775.5	ENSP00000357980.3	Q92743
HTRA1	ENST00000648167.1 link	c.957-36C>T	intron_variant	Intron 8 of 8			ENSP00000498033.1	A0A3B3IU24
HTRA1	ENST00000420892.1 link	c.498-36C>T	intron_variant	Intron 5 of 5	2		ENSP00000412676.1	H0Y7G9

Frequencies

GnomAD3 genomes

AF:

0.185

AC:

28057

AN:

151920

Hom.:

2927

Cov.:

show subpopulations

Gnomad AFR

AF:

0.143

Gnomad AMI

AF:

0.332

Gnomad AMR

AF:

0.211

Gnomad ASJ

AF:

0.218

Gnomad EAS

AF:

0.417

Gnomad SAS

AF:

0.366

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.178

Gnomad OTH

AF:

0.209

GnomAD2 exomes

AF:

0.221

AC:

55644

AN:

251330

AF XY:

0.230

show subpopulations

Gnomad AFR exome

AF:

0.141

Gnomad AMR exome

AF:

0.188

Gnomad ASJ exome

AF:

0.228

Gnomad EAS exome

AF:

0.432

Gnomad FIN exome

AF:

0.133

Gnomad NFE exome

AF:

0.185

Gnomad OTH exome

AF:

0.206

GnomAD4 exome

AF:

0.195

AC:

283440

AN:

1453198

Hom.:

30930

Cov.:

AF XY:

0.201

AC XY:

145665

AN XY:

723596

show subpopulations

African (AFR)

AF:

0.144

AC:

4789

AN:

33288

American (AMR)

AF:

0.191

AC:

8533

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.228

AC:

5941

AN:

26076

East Asian (EAS)

AF:

0.433

AC:

17166

AN:

39652

South Asian (SAS)

AF:

0.370

AC:

31824

AN:

86038

European-Finnish (FIN)

AF:

0.134

AC:

7136

AN:

53382

Middle Eastern (MID)

AF:

0.237

AC:

1201

AN:

5062

European-Non Finnish (NFE)

AF:

0.176

AC:

194319

AN:

1104980

Other (OTH)

AF:

0.209

AC:

12531

AN:

59998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

12832

25664

38496

51328

64160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6988

13976

20964

27952

34940

<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:

0.185

AC:

28070

AN:

152038

Hom.:

2928

Cov.:

AF XY:

0.188

AC XY:

13962

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.143

AC:

5916

AN:

41446

American (AMR)

AF:

0.211

AC:

3224

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.218

AC:

757

AN:

3472

East Asian (EAS)

AF:

0.417

AC:

2153

AN:

5166

South Asian (SAS)

AF:

0.366

AC:

1758

AN:

4802

European-Finnish (FIN)

AF:

0.126

AC:

1332

AN:

10572

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.178

AC:

12108

AN:

67990

Other (OTH)

AF:

0.212

AC:

449

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1124

2248

3373

4497

5621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

312

624

936

1248

1560

<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:

0.177

Hom.:

1835

Bravo

AF:

0.189

Asia WGS

AF:

0.345

AC:

1204

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 23, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31603204, 30859180) -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

3.0

(source)

DANN

Benign

0.44

PhyloP100

-0.25

BranchPoint Hunter

0.0

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over