rs2272599

Variant names:

• chr10-122512079-G-A
• rs2272599
• NM_002775.5:c.1274+14G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002775.5(HTRA1):​c.1274+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.615 in 1,560,700 control chromosomes in the GnomAD database, including 297,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31051 hom., cov: 31)
  • Exomes 𝑓: 0.61 (266191 hom.)
• Consequence: HTRA1 NM_002775.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.55
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-122512079-G-A is Benign according to our data. Variant chr10-122512079-G-A is described in ClinVar as Benign. ClinVar VariationId is 299055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.1274+14G>A		intron_variant	Intron 8 of 8	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.1274+14G>A		intron_variant	Intron 8 of 8	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.956+14G>A		intron_variant	Intron 8 of 8			ENSP00000498033.1
HTRA1	ENST00000420892.1	c.497+14G>A		intron_variant	Intron 5 of 5	2		ENSP00000412676.1

Frequencies

GnomAD3 genomes AF: 0.636 AC: 96631 AN: 151932 Hom.: 31039 Cov.: 31

Gnomad AFR AF: 0.701

Gnomad AMI AF: 0.842

Gnomad AMR AF: 0.548

Gnomad ASJ AF: 0.635

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.620

Gnomad OTH AF: 0.636

GnomAD2 exomes AF: 0.603 AC: 151415 AN: 251216 AF XY: 0.611

Gnomad AFR exome AF: 0.708

Gnomad AMR exome AF: 0.436

Gnomad ASJ exome AF: 0.625

Gnomad EAS exome AF: 0.627

Gnomad FIN exome AF: 0.601

Gnomad NFE exome AF: 0.620

Gnomad OTH exome AF: 0.609

GnomAD4 exome AF: 0.613 AC: 863339 AN: 1408650 Hom.: 266191 Cov.: 23 AF XY: 0.615 AC XY: 433331 AN XY: 704206

African (AFR) AF: 0.704 AC: 22848 AN: 32460

American (AMR) AF: 0.448 AC: 20022 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 16260 AN: 25808

East Asian (EAS) AF: 0.619 AC: 24423 AN: 39426

South Asian (SAS) AF: 0.650 AC: 55322 AN: 85150

European-Finnish (FIN) AF: 0.605 AC: 32266 AN: 53310

Middle Eastern (MID) AF: 0.695 AC: 3894 AN: 5604

European-Non Finnish (NFE) AF: 0.613 AC: 651821 AN: 1063596

Other (OTH) AF: 0.622 AC: 36483 AN: 58650

GnomAD4 genome AF: 0.636 AC: 96676 AN: 152050 Hom.: 31051 Cov.: 31 AF XY: 0.634 AC XY: 47127 AN XY: 74324

African (AFR) AF: 0.700 AC: 29038 AN: 41462

American (AMR) AF: 0.547 AC: 8357 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.635 AC: 2198 AN: 3464

East Asian (EAS) AF: 0.609 AC: 3139 AN: 5154

South Asian (SAS) AF: 0.642 AC: 3088 AN: 4810

European-Finnish (FIN) AF: 0.604 AC: 6386 AN: 10576

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.620 AC: 42145 AN: 67986

Other (OTH) AF: 0.639 AC: 1347 AN: 2108

Alfa AF: 0.622 Hom.: 5491

Bravo AF: 0.631

Asia WGS AF: 0.610 AC: 2126 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CARASIL syndrome Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Macular degeneration Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.84
DANN	Benign	0.80
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs2272599; hg19: chr10-124271595; COSMIC: COSV64564991;