10-122506884-A-C

Variant names:

• chr10-122506884-A-C
• rs1267457680
• NM_002775.5:c.971A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_002775.5(HTRA1):​c.971A>C​(p.Asn324Thr) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N324D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HTRA1 NM_002775.5 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.14
• Publications: 7 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 region_of_interest Serine protease (size 160) in uniprot entity HTRA1_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_002775.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 10-122506884-A-C is Pathogenic according to our data. Variant chr10-122506884-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 523578.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.971A>C	p.Asn324Thr	missense_variant, splice_region_variant	Exon 4 of 9	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.971A>C	p.Asn324Thr	missense_variant, splice_region_variant	Exon 4 of 9	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.653A>C	p.Asn218Thr	missense_variant, splice_region_variant	Exon 4 of 9			ENSP00000498033.1
HTRA1	ENST00000420892.1	c.194A>C	p.Asn65Thr	missense_variant, splice_region_variant	Exon 1 of 6	2		ENSP00000412676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Apr 13, 2018

Taipei Veterans General Hospital, Neurological Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	.;D;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.9	.;M;.
PhyloP100		9.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.7	.;D;D
REVEL	Pathogenic	0.81
Sift	Benign	0.18	.;T;T
Sift4G	Benign	0.20	.;T;T
Polyphen		1.0	.;D;.
Vest4		0.97
MutPred		0.79		.;Gain of glycosylation at N324 (P = 0.144);.;
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		5.2
PromoterAI		-0.042	Neutral
Varity_R		0.74
gMVP		0.94
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
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

Other links and lift over

dbSNP: rs1267457680; hg19: chr10-124266400;