10-122475839-G-C

Variant names:

• chr10-122475839-G-C
• rs2672587
• NM_002775.5:c.473-13063G>C

Variant summary

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

The NM_002775.5(HTRA1):​c.473-13063G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.7 in 152,152 control chromosomes in the GnomAD database, including 37,873 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 0.70 (37873 hom., cov: 33)
• Consequence: HTRA1 NM_002775.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.620
• Publications: 16 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=-0.74).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.473-13063G>C		intron_variant	Intron 1 of 8	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.473-13063G>C		intron_variant	Intron 1 of 8	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.155-13063G>C		intron_variant	Intron 1 of 8			ENSP00000498033.1

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106488 AN: 152034 Hom.: 37859 Cov.: 33

Gnomad AFR AF: 0.639

Gnomad AMI AF: 0.928

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.789

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.733

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.760

Gnomad OTH AF: 0.705

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

GnomAD4 genome AF: 0.700 AC: 106543 AN: 152152 Hom.: 37873 Cov.: 33 AF XY: 0.696 AC XY: 51751 AN XY: 74382

African (AFR) AF: 0.639 AC: 26540 AN: 41524

American (AMR) AF: 0.611 AC: 9337 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.789 AC: 2741 AN: 3472

East Asian (EAS) AF: 0.530 AC: 2721 AN: 5130

South Asian (SAS) AF: 0.653 AC: 3149 AN: 4820

European-Finnish (FIN) AF: 0.733 AC: 7760 AN: 10586

Middle Eastern (MID) AF: 0.806 AC: 237 AN: 294

European-Non Finnish (NFE) AF: 0.760 AC: 51718 AN: 68010

Other (OTH) AF: 0.707 AC: 1494 AN: 2112

Alfa AF: 0.663 Hom.: 16875

Bravo AF: 0.685

Asia WGS AF: 0.563 AC: 1963 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	10
DANN	Benign	0.74
PhyloP100		-0.62
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: rs2672587; hg19: chr10-124235355;