rs554513888

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002775.5(HTRA1):c.-57C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,134,978 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 20 hom., cov: 32)

Exomes 𝑓: 0.017 ( 186 hom. )

Consequence

HTRA1
NM_002775.5 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.03

Publications

1 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:

ENSG00000285955 (HGNC:58122):

ENSG00000285955 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 (REVEL=0.014).

BP6

Variant 10-122461596-C-A is Benign according to our data. Variant chr10-122461596-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 299042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0138 (2041/148090) while in subpopulation NFE AF = 0.0169 (1123/66366). AF 95% confidence interval is 0.0161. There are 20 homozygotes in GnomAd4. There are 951 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5 link	c.-57C>A		5_prime_UTR_variant	Exon 1 of 9	ENST00000368984.8	NP_002766.1	Q92743

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HTRA1	ENST00000368984.8 link	c.-57C>A	5_prime_UTR_variant	Exon 1 of 9	1	NM_002775.5	ENSP00000357980.3	Q92743
HTRA1	ENST00000648167.1 link	c.154+2887C>A	intron_variant	Intron 1 of 8			ENSP00000498033.1	A0A3B3IU24
ENSG00000285955	ENST00000650300.1 link	n.-213G>T	upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.0138

AC:

2041

AN:

147978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00941

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0168

Gnomad ASJ

AF:

0.0351

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.0124

Gnomad FIN

AF:

0.00737

Gnomad MID

AF:

0.0160

Gnomad NFE

AF:

0.0169

Gnomad OTH

AF:

0.0147

GnomAD2 exomes

AF:

0.0145

AC:

998

AN:

68984

AF XY:

0.0149

show subpopulations

Gnomad AFR exome

AF:

0.00882

Gnomad AMR exome

AF:

0.00596

Gnomad ASJ exome

AF:

0.0344

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00727

Gnomad NFE exome

AF:

0.0164

Gnomad OTH exome

AF:

0.0163

GnomAD4 exome

AF:

0.0168

AC:

16540

AN:

986888

Hom.:

186

Cov.:

AF XY:

0.0168

AC XY:

8294

AN XY:

493270

show subpopulations

African (AFR)

AF:

0.00877

AC:

159

AN:

18124

American (AMR)

AF:

0.00749

AC:

143

AN:

19090

Ashkenazi Jewish (ASJ)

AF:

0.0354

AC:

517

AN:

14606

East Asian (EAS)

AF:

0.0000780

AC:

AN:

12824

South Asian (SAS)

AF:

0.0137

AC:

895

AN:

65110

European-Finnish (FIN)

AF:

0.00831

AC:

167

AN:

20094

Middle Eastern (MID)

AF:

0.0153

AC:

AN:

2606

European-Non Finnish (NFE)

AF:

0.0175

AC:

13978

AN:

797464

Other (OTH)

AF:

0.0173

AC:

640

AN:

36970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

730

1459

2189

2918

3648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0138

AC:

2041

AN:

148090

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

951

AN XY:

72120

show subpopulations

African (AFR)

AF:

0.00938

AC:

386

AN:

41144

American (AMR)

AF:

0.0168

AC:

250

AN:

14916

Ashkenazi Jewish (ASJ)

AF:

0.0351

AC:

119

AN:

3394

East Asian (EAS)

AF:

0.000196

AC:

AN:

5108

South Asian (SAS)

AF:

0.0125

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00737

AC:

AN:

9088

Middle Eastern (MID)

AF:

0.0172

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0169

AC:

1123

AN:

66366

Other (OTH)

AF:

0.0146

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

196

294

392

490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0165

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

1.0

PromoterAI

-0.020

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(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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rs554513888

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