rs2272599

Positions:

• chr10-122512079-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id is 299055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-122512079-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.1274+14G>A		intron_variant		ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.1274+14G>A		intron_variant		1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.956+14G>A		intron_variant				ENSP00000498033.1
HTRA1	ENST00000420892.1	c.497+14G>A		intron_variant		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

GnomAD3 exomes AF: 0.603 AC: 151415 AN: 251216 Hom.: 46563 AF XY: 0.611 AC XY: 82970 AN XY: 135826

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 SAS exome AF: 0.648

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

Gnomad4 AFR exome AF: 0.704

Gnomad4 AMR exome AF: 0.448

Gnomad4 ASJ exome AF: 0.630

Gnomad4 EAS exome AF: 0.619

Gnomad4 SAS exome AF: 0.650

Gnomad4 FIN exome AF: 0.605

Gnomad4 NFE exome AF: 0.613

Gnomad4 OTH exome AF: 0.622

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

Gnomad4 AFR AF: 0.700

Gnomad4 AMR AF: 0.547

Gnomad4 ASJ AF: 0.635

Gnomad4 EAS AF: 0.609

Gnomad4 SAS AF: 0.642

Gnomad4 FIN AF: 0.604

Gnomad4 NFE AF: 0.620

Gnomad4 OTH AF: 0.639

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

CARASIL syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Macular degeneration Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

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