10-122488926-G-T

Position:

• chr10-122488926-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The ENST00000368984.8(HTRA1):​c.497G>T​(p.Arg166Leu) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R166C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HTRA1 ENST00000368984.8 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.86

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000368984.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-122488925-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1325819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant 10-122488926-G-T is Pathogenic according to our data. Variant chr10-122488926-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 221228.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.497G>T	p.Arg166Leu	missense_variant	2/9	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.497G>T	p.Arg166Leu	missense_variant	2/9	1	NM_002775.5	ENSP00000357980	P1
HTRA1	ENST00000648167.1	c.179G>T	p.Arg60Leu	missense_variant	2/9			ENSP00000498033

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26063658). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 0.81). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with HTRA1-related disorder (ClinVar ID: VCV000221228 / PMID: 26063658). A different missense change at the same codon (p.Arg166Cys) has been reported to be associated with HTRA1-related disorder (ClinVar ID: VCV001325819 / PMID: 25712943). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	.;T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.8	.;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.9	.;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	.;D
Sift4G	Pathogenic	0.0010	.;D
Polyphen		1.0	.;D
Vest4		0.96
MutPred		0.54		.;Gain of ubiquitination at K168 (P = 0.0846);
MVP		0.97
MPC		1.6
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs864622781; hg19: chr10-124248442;