rs2672589

Variant names:

• chr10-122475472-G-A
• rs2672589
• NM_002775.5:c.472+13348G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-122475472-G-A
• chr10-122475472-G-C
• chr10-122475472-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002775.5(HTRA1):​c.472+13348G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 152,250 control chromosomes in the GnomAD database, including 31,799 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.64 (31799 hom., cov: 35)
• Consequence: HTRA1 NM_002775.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.617
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
• 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: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 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.472+13348G>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.472+13348G>A		intron	N/A	ENSP00000357980.3	Q92743
	HTRA1	ENST00000869938.1		c.472+13348G>A		intron	N/A	ENSP00000539997.1
	HTRA1	ENST00000962536.1		c.472+13348G>A		intron	N/A	ENSP00000632595.1

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97823 AN: 152132 Hom.: 31756 Cov.: 35

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.670

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.761

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.576

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.613

Gnomad OTH AF: 0.633

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.643 AC: 97927 AN: 152250 Hom.: 31799 Cov.: 35 AF XY: 0.641 AC XY: 47681 AN XY: 74432

African (AFR) AF: 0.730 AC: 30331 AN: 41562

American (AMR) AF: 0.568 AC: 8694 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 2089 AN: 3468

East Asian (EAS) AF: 0.762 AC: 3937 AN: 5170

South Asian (SAS) AF: 0.623 AC: 3007 AN: 4830

European-Finnish (FIN) AF: 0.576 AC: 6090 AN: 10582

Middle Eastern (MID) AF: 0.555 AC: 162 AN: 292

European-Non Finnish (NFE) AF: 0.613 AC: 41676 AN: 68020

Other (OTH) AF: 0.630 AC: 1331 AN: 2114

Alfa AF: 0.628 Hom.: 52190

Bravo AF: 0.644

Asia WGS AF: 0.699 AC: 2427 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.4
DANN	Benign	0.46
PhyloP100		-0.62
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: rs2672589; hg19: chr10-124234988;