rs1554950703

Variant names:

• chr10-122489463-C-G
• rs1554950703
• NM_002775.5:c.614C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_002775.5(HTRA1):​c.614C>G​(p.Ser205Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HTRA1 NM_002775.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.79
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a region_of_interest Serine protease (size 160) in uniprot entity HTRA1_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_002775.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 10-122489463-C-G is Pathogenic according to our data. Variant chr10-122489463-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 560164.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.614C>G	p.Ser205Cys	missense_variant	Exon 3 of 9	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.614C>G	p.Ser205Cys	missense_variant	Exon 3 of 9	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.296C>G	p.Ser99Cys	missense_variant	Exon 3 of 9			ENSP00000498033.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

CARASIL syndrome Pathogenic:1

Apr 18, 2018

Department of Clinical Laboratory, Peking University People's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;in vitro

Cerebral autosomal recessive arterial disease with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare inherited cerebral artery disease, which is characterized by ischemic, non-hypertensive, cerebral small-vessel disease with associated alopecia and spondylosis. It has been established that the high temperature requirement serine peptidase A1 (HTRA1) gene is a causative agent of CARASIL and represses signaling pathway transforming growth factor β1 (TGF-β1)/Smads. To date, 4 missense mutations and 2 nonsense mutations had been reported and they were distributed in exon3, 4 and 6 where located the HTRA1 protease domain, which might lead to the change of HTRA1 gene activity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	.;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	.;H
PhyloP100		7.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.0	.;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	.;D
Vest4		0.93
MutPred		0.78		.;Loss of glycosylation at S205 (P = 0.0046);
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.94
gMVP		0.90
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554950703; hg19: chr10-124248979;