10-122474804-G-A

Variant names:

• chr10-122474804-G-A
• rs4752699
• NM_002775.5:c.472+12680G>A

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+12680G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,122 control chromosomes in the GnomAD database, including 1,521 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 0.14 (1521 hom., cov: 33)
• Consequence: HTRA1 NM_002775.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.310
• Publications: 11 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.218 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTRA1	NM_002775.5	MANE Select	c.472+12680G>A		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.472+12680G>A		intron	N/A	ENSP00000357980.3
	HTRA1	ENST00000648167.1		c.155-14098G>A		intron	N/A	ENSP00000498033.1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20675 AN: 152004 Hom.: 1517 Cov.: 33

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.146

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

GnomAD4 genome AF: 0.136 AC: 20699 AN: 152122 Hom.: 1521 Cov.: 33 AF XY: 0.135 AC XY: 10069 AN XY: 74352

African (AFR) AF: 0.101 AC: 4211 AN: 41506

American (AMR) AF: 0.134 AC: 2041 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 742 AN: 3470

East Asian (EAS) AF: 0.229 AC: 1185 AN: 5172

South Asian (SAS) AF: 0.194 AC: 935 AN: 4824

European-Finnish (FIN) AF: 0.102 AC: 1076 AN: 10578

Middle Eastern (MID) AF: 0.229 AC: 67 AN: 292

European-Non Finnish (NFE) AF: 0.146 AC: 9926 AN: 67986

Other (OTH) AF: 0.144 AC: 304 AN: 2110

Alfa AF: 0.143 Hom.: 2078

Bravo AF: 0.135

Asia WGS AF: 0.177 AC: 614 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.95
DANN	Benign	0.40
PhyloP100		0.31
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: rs4752699; hg19: chr10-124234320;