rs864622782

Positions:

• chr10-122506765-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_002775.5(HTRA1):​c.852C>A​(p.Ser284Arg) 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 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. S284G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HTRA1 NM_002775.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.821

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a region_of_interest Serine protease (size 160) in uniprot entity HTRA1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_002775.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 10-122506765-C-A is Pathogenic according to our data. Variant chr10-122506765-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 221230.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.852C>A	p.Ser284Arg	missense_variant	4/9	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.852C>A	p.Ser284Arg	missense_variant	4/9	1	NM_002775.5	ENSP00000357980	P1
HTRA1	ENST00000648167.1	c.534C>A	p.Ser178Arg	missense_variant	4/9			ENSP00000498033
HTRA1	ENST00000420892.1	c.75C>A	p.Ser25Arg	missense_variant	1/6	2		ENSP00000412676

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 21, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	.;D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	3.0	.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.8	.;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0010	.;D;D
Polyphen		1.0	.;D;.
Vest4		0.99
MutPred		0.81		.;Loss of sheet (P = 0.0228);.;
MVP		0.90
MPC		1.5
ClinPred		1.0	D
GERP RS		2.0
Varity_R		0.99
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs864622782; hg19: chr10-124266281;