chr10-122459759-C-G

Variant names:

• chr10-122459759-C-G
• rs3793917
• ENST00000650300.1:n.588G>C

Variant summary

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

The ENST00000650300.1(ENSG00000285955):​n.588G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 151,962 control chromosomes in the GnomAD database, including 4,464 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 0.24 (4464 hom., cov: 31)
• Consequence: ENSG00000285955 ENST00000650300.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.405
• Publications: 63 publications found

Genes affected

ENSG00000285955 (HGNC:58122):

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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000650300.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000285955	ENST00000650300.1		n.588G>C		non_coding_transcript_exon	Exon 2 of 3
	HTRA1	ENST00000648167.1		c.154+1050C>G		intron	N/A	ENSP00000498033.1

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35892 AN: 151844 Hom.: 4456 Cov.: 31

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.239

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

GnomAD4 genome AF: 0.237 AC: 35941 AN: 151962 Hom.: 4464 Cov.: 31 AF XY: 0.239 AC XY: 17777 AN XY: 74280

African (AFR) AF: 0.235 AC: 9761 AN: 41450

American (AMR) AF: 0.232 AC: 3543 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 722 AN: 3466

East Asian (EAS) AF: 0.424 AC: 2175 AN: 5130

South Asian (SAS) AF: 0.319 AC: 1532 AN: 4806

European-Finnish (FIN) AF: 0.236 AC: 2492 AN: 10568

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14896 AN: 67948

Other (OTH) AF: 0.236 AC: 498 AN: 2108

Alfa AF: 0.149 Hom.: 298

Bravo AF: 0.239

Asia WGS AF: 0.371 AC: 1285 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.84
DANN	Benign	0.41
PhyloP100		-0.41

Splicing

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

Other links and lift over

dbSNP: rs3793917; hg19: chr10-124219275;