chr10-122490577-G-C

Variant names:

• chr10-122490577-G-C
• rs2239588
• NM_002775.5:c.777+951G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_002775.5(HTRA1):​c.777+951G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 152,120 control chromosomes in the GnomAD database, including 1,225 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 0.12 (1225 hom., cov: 32)
• Consequence: HTRA1 NM_002775.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 5 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.777+951G>C		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+951G>C		intron_variant	Intron 3 of 8	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.459+951G>C		intron_variant	Intron 3 of 8			ENSP00000498033.1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17483 AN: 152002 Hom.: 1222 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.0750

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.0928

Gnomad OTH AF: 0.131

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

GnomAD4 genome AF: 0.115 AC: 17515 AN: 152120 Hom.: 1225 Cov.: 32 AF XY: 0.120 AC XY: 8937 AN XY: 74332

African (AFR) AF: 0.103 AC: 4257 AN: 41516

American (AMR) AF: 0.156 AC: 2377 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 491 AN: 3470

East Asian (EAS) AF: 0.224 AC: 1153 AN: 5156

South Asian (SAS) AF: 0.321 AC: 1540 AN: 4796

European-Finnish (FIN) AF: 0.0750 AC: 793 AN: 10580

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.0928 AC: 6310 AN: 68006

Other (OTH) AF: 0.133 AC: 281 AN: 2110

Alfa AF: 0.0379 Hom.: 24

Bravo AF: 0.117

Asia WGS AF: 0.255 AC: 892 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	17
DANN	Benign	0.81
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2239588; hg19: chr10-124250093;