rs587776447

Positions:

• chr10-122508741-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_002775.5(HTRA1):​c.1091T>C​(p.Leu364Pro) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HTRA1 NM_002775.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.81

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 8 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, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTRA1	NM_002775.5	c.1091T>C	p.Leu364Pro	missense_variant	6/9	ENST00000368984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTRA1	ENST00000368984.8	c.1091T>C	p.Leu364Pro	missense_variant	6/9	1	NM_002775.5	P1
HTRA1	ENST00000648167.1	c.773T>C	p.Leu258Pro	missense_variant	6/9
HTRA1	ENST00000420892.1	c.314T>C	p.Leu105Pro	missense_variant	3/6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

CARASIL syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	.;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.9	.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.6	.;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0010	.;D;D
Polyphen		1.0	.;D;.
Vest4		0.97
MutPred		0.80		.;Gain of disorder (P = 0.0256);.;
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.99

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: rs587776447; hg19: chr10-124268257;