10-122504516-A-G

Variant names:

• chr10-122504516-A-G
• rs909290
• NM_002775.5:c.778-2175A>G

Variant summary

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

The NM_002775.5(HTRA1):​c.778-2175A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.822 in 152,140 control chromosomes in the GnomAD database, including 51,903 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 (51903 hom., cov: 32)
• Consequence: HTRA1 NM_002775.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.222
• Publications: 4 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.881 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.778-2175A>G		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.778-2175A>G		intron	N/A	ENSP00000357980.3	Q92743
	HTRA1	ENST00000869938.1		c.778-2175A>G		intron	N/A	ENSP00000539997.1
	HTRA1	ENST00000962536.1		c.778-2181A>G		intron	N/A	ENSP00000632595.1

Frequencies

GnomAD3 genomes AF: 0.822 AC: 125037 AN: 152022 Hom.: 51901 Cov.: 32

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.815

Gnomad EAS AF: 0.639

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.910

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.886

Gnomad OTH AF: 0.814

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

GnomAD4 genome AF: 0.822 AC: 125079 AN: 152140 Hom.: 51903 Cov.: 32 AF XY: 0.818 AC XY: 60807 AN XY: 74380

African (AFR) AF: 0.744 AC: 30858 AN: 41488

American (AMR) AF: 0.812 AC: 12419 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 2831 AN: 3472

East Asian (EAS) AF: 0.638 AC: 3275 AN: 5130

South Asian (SAS) AF: 0.655 AC: 3160 AN: 4824

European-Finnish (FIN) AF: 0.910 AC: 9655 AN: 10606

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.886 AC: 60288 AN: 68010

Other (OTH) AF: 0.810 AC: 1715 AN: 2116

Alfa AF: 0.854 Hom.: 6911

Bravo AF: 0.813

Asia WGS AF: 0.673 AC: 2339 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.4
DANN	Benign	0.54
PhyloP100		-0.22
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: rs909290; hg19: chr10-124264032;