Genetic Variant NM_002775.5:c.753C>T (chr10-122489602-C-T) – ACMG Classification: Benign (-19 pts)

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

Clinical Significance

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

Conservation

PhyloP100: 0.232

Publications

10 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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
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: Orphanet, Ambry Genetics

HTRA1 links:

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 VariationId is 100572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002775.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA1	NM_002775.5	MANE Select	c.753C>T	p.Ile251Ile	synonymous	Exon 3 of 9	NP_002766.1	Q92743

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HTRA1	ENST00000368984.8	TSL:1 MANE Select	c.753C>T	p.Ile251Ile	synonymous	Exon 3 of 9	ENSP00000357980.3	Q92743
HTRA1	ENST00000869938.1		c.753C>T	p.Ile251Ile	synonymous	Exon 3 of 9	ENSP00000539997.1
HTRA1	ENST00000962536.1		c.753C>T	p.Ile251Ile	synonymous	Exon 3 of 9	ENSP00000632595.1

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

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.:

AF XY:

0.0508

AC XY:

36901

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.0264

AC:

885

AN:

33468

American (AMR)

AF:

0.0163

AC:

727

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0292

AC:

763

AN:

26132

East Asian (EAS)

AF:

0.000403

AC:

AN:

39700

South Asian (SAS)

AF:

0.0425

AC:

3665

AN:

86234

European-Finnish (FIN)

AF:

0.0698

AC:

3729

AN:

53420

Middle Eastern (MID)

AF:

0.0481

AC:

272

AN:

5650

European-Non Finnish (NFE)

AF:

0.0551

AC:

61259

AN:

1111854

Other (OTH)

AF:

0.0446

AC:

2695

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

4088

8177

12265

16354

20442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

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.:

AF XY:

0.0415

AC XY:

3086

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0272

AC:

1129

AN:

41524

American (AMR)

AF:

0.0230

AC:

351

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0302

AC:

105

AN:

3472

East Asian (EAS)

AF:

0.000971

AC:

AN:

5150

South Asian (SAS)

AF:

0.0442

AC:

213

AN:

4824

European-Finnish (FIN)

AF:

0.0743

AC:

787

AN:

10596

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0512

AC:

3481

AN:

68010

Other (OTH)

AF:

0.0345

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

307

614

920

1227

1534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

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:

AN:

3478

EpiCase

AF:

0.0504

EpiControl

AF:

0.0468

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Macular degeneration (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

0.52

(source)

DANN

Benign

0.71

PhyloP100

0.23

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over