rs2293871

Positions:

• chr10-122514155-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002775.5(HTRA1):​c.1275-36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,605,236 control chromosomes in the GnomAD database, including 33,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.18 (2928 hom., cov: 31)
  • Exomes 𝑓: 0.20 (30930 hom.)
• Consequence: HTRA1 NM_002775.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.246

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 0 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-122514155-C-T is Benign according to our data. Variant chr10-122514155-C-T is described in ClinVar as [Benign]. Clinvar id is 1259856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTRA1	NM_002775.5	c.1275-36C>T		intron_variant		ENST00000368984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTRA1	ENST00000368984.8	c.1275-36C>T		intron_variant		1	NM_002775.5	P1
HTRA1	ENST00000420892.1	c.498-36C>T		intron_variant		2
HTRA1	ENST00000648167.1	c.957-36C>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28057 AN: 151920 Hom.: 2927 Cov.: 31

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.209

GnomAD3 exomes AF: 0.221 AC: 55644 AN: 251330 Hom.: 7292 AF XY: 0.230 AC XY: 31266 AN XY: 135842

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.228

Gnomad EAS exome AF: 0.432

Gnomad SAS exome AF: 0.373

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.195 AC: 283440 AN: 1453198 Hom.: 30930 Cov.: 29 AF XY: 0.201 AC XY: 145665 AN XY: 723596

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.191

Gnomad4 ASJ exome AF: 0.228

Gnomad4 EAS exome AF: 0.433

Gnomad4 SAS exome AF: 0.370

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.185 AC: 28070 AN: 152038 Hom.: 2928 Cov.: 31 AF XY: 0.188 AC XY: 13962 AN XY: 74296

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.211

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.417

Gnomad4 SAS AF: 0.366

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.212

Alfa AF: 0.177 Hom.: 1835

Bravo AF: 0.189

Asia WGS AF: 0.345 AC: 1204 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 23, 2019

This variant is associated with the following publications: (PMID: 31603204, 30859180) -

CARASIL syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.0
DANN	Benign	0.44
BranchPoint Hunter		0.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs2293871; hg19: chr10-124273671; COSMIC: COSV64563219;