NM_002775.5:c.517G>C

Variant names:

• chr10-122488946-G-C
• rs781563777
• NM_002775.5:c.517G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_002775.5(HTRA1):​c.517G>C​(p.Ala173Pro) 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A173V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HTRA1 NM_002775.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.83
• Publications: 13 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_002775.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• PP5: Variant 10-122488946-G-C is Pathogenic according to our data. Variant chr10-122488946-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 221229.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.517G>C	p.Ala173Pro	missense_variant	Exon 2 of 9	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.517G>C	p.Ala173Pro	missense_variant	Exon 2 of 9	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.199G>C	p.Ala67Pro	missense_variant	Exon 2 of 9			ENSP00000498033.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 Pathogenic:1

Sep 21, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.8	.;M
PhyloP100		9.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.2	.;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0020	.;D
Polyphen		0.99	.;D
Vest4		0.98
MutPred		0.59		.;Loss of stability (P = 0.0356);
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.98
Mutation Taster		=16/84	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs781563777; hg19: chr10-124248462;