rs1554950703

chr10-122489463-C-G

Variant summary

Our verdict is Pathogenic. Variant got 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a region_of_interest Serine protease (size 160) in uniprot entity HTRA1_HUMAN there are 20 pathogenic changes around while only 3 benign (87%) 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 id is 560164.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTRA1	NM_002775.5	c.614C>G	p.Ser205Cys	missense_variant	3/9	ENST00000368984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTRA1	ENST00000368984.8	c.614C>G	p.Ser205Cys	missense_variant	3/9	1	NM_002775.5	P1
HTRA1	ENST00000648167.1	c.296C>G	p.Ser99Cys	missense_variant	3/9

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

Pathogenic, criteria provided, single submitter

clinical testing;in vitro

Department of Clinical Laboratory, Peking University People's Hospital

Apr 18, 2018

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
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
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554950703; hg19: chr10-124248979;