rs2672585

Variant names:

• chr10-122508885-C-G
• rs2672585
• NM_002775.5:c.1120+115C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002775.5(HTRA1):​c.1120+115C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 717,230 control chromosomes in the GnomAD database, including 40,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.30 (7325 hom., cov: 32)
  • Exomes 𝑓: 0.33 (32780 hom.)
• Consequence: HTRA1 NM_002775.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.30
• Publications: 9 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, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-122508885-C-G is Benign according to our data. Variant chr10-122508885-C-G is described in ClinVar as Benign. ClinVar VariationId is 1246855.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.409 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.1120+115C>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.1120+115C>G		intron	N/A	ENSP00000357980.3	Q92743
	HTRA1	ENST00000869938.1		c.1120+115C>G		intron	N/A	ENSP00000539997.1
	HTRA1	ENST00000962536.1		c.1114+115C>G		intron	N/A	ENSP00000632595.1

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45085 AN: 151956 Hom.: 7310 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.302

GnomAD4 exome AF: 0.333 AC: 188081 AN: 565154 Hom.: 32780 AF XY: 0.328 AC XY: 100053 AN XY: 305416

African (AFR) AF: 0.184 AC: 2931 AN: 15956

American (AMR) AF: 0.521 AC: 18461 AN: 35436

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 5954 AN: 19682

East Asian (EAS) AF: 0.378 AC: 12710 AN: 33586

South Asian (SAS) AF: 0.299 AC: 19408 AN: 64962

European-Finnish (FIN) AF: 0.320 AC: 12710 AN: 39746

Middle Eastern (MID) AF: 0.234 AC: 622 AN: 2656

European-Non Finnish (NFE) AF: 0.327 AC: 105547 AN: 322634

Other (OTH) AF: 0.319 AC: 9738 AN: 30496

GnomAD4 genome AF: 0.297 AC: 45126 AN: 152076 Hom.: 7325 Cov.: 32 AF XY: 0.299 AC XY: 22197 AN XY: 74324

African (AFR) AF: 0.188 AC: 7799 AN: 41492

American (AMR) AF: 0.418 AC: 6382 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1022 AN: 3470

East Asian (EAS) AF: 0.385 AC: 1981 AN: 5152

South Asian (SAS) AF: 0.299 AC: 1438 AN: 4808

European-Finnish (FIN) AF: 0.322 AC: 3397 AN: 10562

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22316 AN: 67994

Other (OTH) AF: 0.300 AC: 632 AN: 2108

Alfa AF: 0.318 Hom.: 995

Bravo AF: 0.303

Asia WGS AF: 0.359 AC: 1244 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.055
DANN	Benign	0.41
PhyloP100		-1.3
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: rs2672585; hg19: chr10-124268401; COSMIC: COSV64565073;