Genetic Variant HTRA1:p.Leu24Val (chr10-122461722-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002775.5(HTRA1):c.70C>G(p.Leu24Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L24L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.5e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HTRA1
NM_002775.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.27

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07095823).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5 link	c.70C>G	p.Leu24Val	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.70C>G	p.Leu24Val	missense_variant	Exon 1 of 9	1	NM_002775.5	ENSP00000357980.3		Q92743
HTRA1	ENST00000648167.1 link	c.154+3013C>G		intron_variant	Intron 1 of 8			ENSP00000498033.1		A0A3B3IU24

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000175

AC:

AN:

57146

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000459

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.52e-7

AC:

AN:

1050688

Hom.:

Cov.:

AF XY:

0.00000195

AC XY:

AN XY:

512798

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19822

American (AMR)

AF:

0.00

AC:

AN:

13138

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13256

East Asian (EAS)

AF:

0.00

AC:

AN:

13866

South Asian (SAS)

AF:

0.00

AC:

AN:

46738

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2574

European-Non Finnish (NFE)

AF:

0.00000113

AC:

AN:

887840

Other (OTH)

AF:

0.00

AC:

AN:

37852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.094

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.39

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.071

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

PhyloP100

1.3

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.50

REVEL

Benign

0.21

Sift

Benign

0.62

Sift4G

Benign

0.46

Polyphen

0.0030

Vest4

0.053

MutPred

0.25

Loss of helix (P = 0.0033);

MVP

0.73

MPC

0.51

ClinPred

0.042

GERP RS

2.9

PromoterAI

-0.26

Neutral

(source)

Varity_R

0.052

gMVP

0.37

Mutation Taster

=88/12

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

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over