Genetic Variant NM_002775.5:c.10C>G (chr10-122461662-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.10C>G(p.Pro4Ala) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HTRA1
NM_002775.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.313

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: 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:

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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=0.16170713).

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.10C>G	p.Pro4Ala	missense	Exon 1 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.10C>G	p.Pro4Ala	missense	Exon 1 of 9	ENSP00000357980.3	Q92743
HTRA1	ENST00000869938.1		c.10C>G	p.Pro4Ala	missense	Exon 1 of 9	ENSP00000539997.1
HTRA1	ENST00000962536.1		c.10C>G	p.Pro4Ala	missense	Exon 1 of 9	ENSP00000632595.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1165794

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

574390

African (AFR)

AF:

0.00

AC:

AN:

22050

American (AMR)

AF:

0.00

AC:

AN:

22008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16806

East Asian (EAS)

AF:

0.00

AC:

AN:

16308

South Asian (SAS)

AF:

0.00

AC:

AN:

69260

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3060

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

950076

Other (OTH)

AF:

0.00

AC:

AN:

43928

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

9.1

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.082

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.45

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.0

PhyloP100

0.31

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.34

REVEL

Benign

0.26

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0

Vest4

0.070

MutPred

0.24

Loss of loop (P = 9e-04)

MVP

0.85

MPC

0.49

ClinPred

0.080

GERP RS

1.6

PromoterAI

0.037

Neutral

(source)

Varity_R

0.067

gMVP

0.44

Mutation Taster

=91/9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over