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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002775.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA1	NM_002775.5	MANE Select	c.1274+14G>A		intron	N/A	NP_002766.1	Q92743

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA1	ENST00000368984.8	TSL:1 MANE Select	c.1274+14G>A		intron	N/A	ENSP00000357980.3	Q92743
	HTRA1	ENST00000869938.1		c.1277+14G>A		intron	N/A	ENSP00000539997.1
	HTRA1	ENST00000962536.1		c.1268+14G>A		intron	N/A	ENSP00000632595.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	CARASIL syndrome (1)
-	-	1	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 (1)
-	-	1	Macular degeneration (1)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2272599;

hg19: chr10-124271595;

COSMIC: COSV64564991;