rs2672583

Variant names:

• chr10-122507571-G-A
• rs2672583
• NM_002775.5:c.1005+169G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-122507571-G-A
• chr10-122507571-G-C
• chr10-122507571-G-T

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.1005+169G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 152,042 control chromosomes in the GnomAD database, including 7,128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.29 (7128 hom., cov: 32)
• Consequence: HTRA1 NM_002775.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.18
• 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: 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=-0.99).
• BP6: Variant 10-122507571-G-A is Benign according to our data. Variant chr10-122507571-G-A is described in ClinVar as Benign. ClinVar VariationId is 1296786.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.1005+169G>A		intron_variant	Intron 5 of 8	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.1005+169G>A		intron_variant	Intron 5 of 8	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.687+169G>A		intron_variant	Intron 5 of 8			ENSP00000498033.1
HTRA1	ENST00000420892.1	c.228+169G>A		intron_variant	Intron 2 of 5	2		ENSP00000412676.1

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44263 AN: 151926 Hom.: 7119 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.297

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

GnomAD4 genome AF: 0.291 AC: 44295 AN: 152042 Hom.: 7128 Cov.: 32 AF XY: 0.294 AC XY: 21822 AN XY: 74328

African (AFR) AF: 0.172 AC: 7116 AN: 41478

American (AMR) AF: 0.409 AC: 6245 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1020 AN: 3470

East Asian (EAS) AF: 0.384 AC: 1984 AN: 5172

South Asian (SAS) AF: 0.300 AC: 1443 AN: 4816

European-Finnish (FIN) AF: 0.322 AC: 3403 AN: 10556

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22305 AN: 67982

Other (OTH) AF: 0.295 AC: 621 AN: 2108

Alfa AF: 0.277 Hom.: 2067

Bravo AF: 0.295

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

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	-0.99
CADD	Benign	0.021
DANN	Benign	0.61
PhyloP100		-2.2
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: rs2672583; hg19: chr10-124267087;