rs2239587

Variant names:

• chr10-122489793-G-A
• rs2239587
• NM_002775.5:c.777+167G>A

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.777+167G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 151,934 control chromosomes in the GnomAD database, including 1,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.15 (1955 hom., cov: 32)
• Consequence: HTRA1 NM_002775.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.176
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 10-122489793-G-A is Benign according to our data. Variant chr10-122489793-G-A is described in ClinVar as Benign. ClinVar VariationId is 1245621.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.777+167G>A		intron_variant	Intron 3 of 8	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.777+167G>A		intron_variant	Intron 3 of 8	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.459+167G>A		intron_variant	Intron 3 of 8			ENSP00000498033.1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22401 AN: 151816 Hom.: 1948 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.0905

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.158

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

GnomAD4 genome AF: 0.148 AC: 22445 AN: 151934 Hom.: 1955 Cov.: 32 AF XY: 0.152 AC XY: 11316 AN XY: 74270

African (AFR) AF: 0.161 AC: 6676 AN: 41418

American (AMR) AF: 0.170 AC: 2598 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 459 AN: 3468

East Asian (EAS) AF: 0.367 AC: 1893 AN: 5162

South Asian (SAS) AF: 0.342 AC: 1638 AN: 4790

European-Finnish (FIN) AF: 0.0905 AC: 957 AN: 10574

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7569 AN: 67942

Other (OTH) AF: 0.160 AC: 337 AN: 2104

Alfa AF: 0.144 Hom.: 555

Bravo AF: 0.153

Asia WGS AF: 0.320 AC: 1116 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.3
DANN	Benign	0.61
PhyloP100		-0.18
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: rs2239587; hg19: chr10-124249309; COSMIC: COSV64565254;