rs2672586

Variant names:

• chr10-122512073-G-A
• rs2672586
• NM_002775.5:c.1274+8G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-122512073-G-A
• chr10-122512073-G-C
• chr10-122512073-G-T

Variant summary

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

The ENST00000368984.8(HTRA1):​c.1274+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,586,922 control chromosomes in the GnomAD database, including 793,253 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (76039 hom., cov: 31)
  • Exomes 𝑓: 1.0 (717214 hom.)
• Consequence: HTRA1 ENST00000368984.8 splice_region, intron
• Scores: Splicing: ADA: 0.0001040
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.10
• Publications: 12 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=-0.75).
• BP6: Variant 10-122512073-G-A is Benign according to our data. Variant chr10-122512073-G-A is described in ClinVar as Benign. ClinVar VariationId is 299054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000368984.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA1	NM_002775.5	MANE Select	c.1274+8G>A		splice_region intron	N/A	NP_002766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA1	ENST00000368984.8	TSL:1 MANE Select	c.1274+8G>A		splice_region intron	N/A	ENSP00000357980.3
	HTRA1	ENST00000648167.1		c.956+8G>A		splice_region intron	N/A	ENSP00000498033.1
	HTRA1	ENST00000420892.1	TSL:2	c.497+8G>A		splice_region intron	N/A	ENSP00000412676.1

Frequencies

GnomAD3 genomes AF: 0.999 AC: 152048 AN: 152132 Hom.: 75982 Cov.: 31

Gnomad AFR AF: 0.998

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.999

GnomAD2 exomes AF: 1.00 AC: 251368 AN: 251408 AF XY: 1.00

Gnomad AFR exome AF: 0.998

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 1.00 AC: 1434548 AN: 1434670 Hom.: 717214 Cov.: 25 AF XY: 1.00 AC XY: 715579 AN XY: 715634

African (AFR) AF: 0.998 AC: 32889 AN: 32960

American (AMR) AF: 1.00 AC: 44673 AN: 44686

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 25982 AN: 25982

East Asian (EAS) AF: 1.00 AC: 39548 AN: 39548

South Asian (SAS) AF: 1.00 AC: 85694 AN: 85696

European-Finnish (FIN) AF: 1.00 AC: 53372 AN: 53372

Middle Eastern (MID) AF: 0.999 AC: 5665 AN: 5670

European-Non Finnish (NFE) AF: 1.00 AC: 1087281 AN: 1087294

Other (OTH) AF: 1.00 AC: 59444 AN: 59462

GnomAD4 genome AF: 0.999 AC: 152165 AN: 152252 Hom.: 76039 Cov.: 31 AF XY: 1.00 AC XY: 74405 AN XY: 74440

African (AFR) AF: 0.998 AC: 41478 AN: 41558

American (AMR) AF: 1.00 AC: 15294 AN: 15298

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3470 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5158 AN: 5158

South Asian (SAS) AF: 1.00 AC: 4806 AN: 4806

European-Finnish (FIN) AF: 1.00 AC: 10608 AN: 10608

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68031 AN: 68032

Other (OTH) AF: 0.999 AC: 2114 AN: 2116

Alfa AF: 1.00 Hom.: 32783

Bravo AF: 0.999

Asia WGS AF: 0.999 AC: 3476 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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	-0.75
CADD	Benign	0.80
DANN	Benign	0.77
PhyloP100		-1.1
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.076
SpliceAI score (max)		0.040		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: rs2672586; hg19: chr10-124271589;