rs2736917

Variant names:

• chr10-122479467-G-A
• rs2736917
• NM_002775.5:c.473-9435G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-122479467-G-A
• chr10-122479467-G-C

Variant summary

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

The NM_002775.5(HTRA1):​c.473-9435G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.815 in 152,036 control chromosomes in the GnomAD database, including 50,682 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 0.82 (50682 hom., cov: 33)
• Consequence: HTRA1 NM_002775.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0950
• 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.473-9435G>A		intron_variant	Intron 1 of 8	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.473-9435G>A		intron_variant	Intron 1 of 8	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.155-9435G>A		intron_variant	Intron 1 of 8			ENSP00000498033.1

Frequencies

GnomAD3 genomes AF: 0.815 AC: 123869 AN: 151918 Hom.: 50631 Cov.: 33

Gnomad AFR AF: 0.851

Gnomad AMI AF: 0.815

Gnomad AMR AF: 0.859

Gnomad ASJ AF: 0.800

Gnomad EAS AF: 0.807

Gnomad SAS AF: 0.873

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.850

Gnomad NFE AF: 0.800

Gnomad OTH AF: 0.818

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

GnomAD4 genome AF: 0.815 AC: 123977 AN: 152036 Hom.: 50682 Cov.: 33 AF XY: 0.813 AC XY: 60434 AN XY: 74306

African (AFR) AF: 0.851 AC: 35264 AN: 41432

American (AMR) AF: 0.859 AC: 13135 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.800 AC: 2772 AN: 3464

East Asian (EAS) AF: 0.808 AC: 4177 AN: 5172

South Asian (SAS) AF: 0.873 AC: 4210 AN: 4822

European-Finnish (FIN) AF: 0.694 AC: 7325 AN: 10548

Middle Eastern (MID) AF: 0.842 AC: 246 AN: 292

European-Non Finnish (NFE) AF: 0.800 AC: 54385 AN: 67986

Other (OTH) AF: 0.814 AC: 1720 AN: 2112

Alfa AF: 0.809 Hom.: 18687

Bravo AF: 0.831

Asia WGS AF: 0.833 AC: 2897 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	4.2
DANN	Benign	0.58
PhyloP100		-0.095
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2736917; hg19: chr10-124238983;