10-122514155-C-T

Variant names:

• chr10-122514155-C-T
• rs2293871
• NM_002775.5:c.1275-36C>T

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: -0.246
• Publications: 15 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. 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 VariationId 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 rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.1275-36C>T		intron_variant	Intron 8 of 8	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.1275-36C>T		intron_variant	Intron 8 of 8	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.957-36C>T		intron_variant	Intron 8 of 8			ENSP00000498033.1
HTRA1	ENST00000420892.1	c.498-36C>T		intron_variant	Intron 5 of 5	2		ENSP00000412676.1

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

GnomAD2 exomes AF: 0.221 AC: 55644 AN: 251330 AF XY: 0.230

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 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

African (AFR) AF: 0.144 AC: 4789 AN: 33288

American (AMR) AF: 0.191 AC: 8533 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 5941 AN: 26076

East Asian (EAS) AF: 0.433 AC: 17166 AN: 39652

South Asian (SAS) AF: 0.370 AC: 31824 AN: 86038

European-Finnish (FIN) AF: 0.134 AC: 7136 AN: 53382

Middle Eastern (MID) AF: 0.237 AC: 1201 AN: 5062

European-Non Finnish (NFE) AF: 0.176 AC: 194319 AN: 1104980

Other (OTH) AF: 0.209 AC: 12531 AN: 59998

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

African (AFR) AF: 0.143 AC: 5916 AN: 41446

American (AMR) AF: 0.211 AC: 3224 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 757 AN: 3472

East Asian (EAS) AF: 0.417 AC: 2153 AN: 5166

South Asian (SAS) AF: 0.366 AC: 1758 AN: 4802

European-Finnish (FIN) AF: 0.126 AC: 1332 AN: 10572

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12108 AN: 67990

Other (OTH) AF: 0.212 AC: 449 AN: 2114

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 23, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CARASIL syndrome Benign:1

Aug 10, 2021

Genome-Nilou Lab

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	-0.88
CADD	Benign	3.0
DANN	Benign	0.44
PhyloP100		-0.25
BranchPoint Hunter		0.0
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: rs2293871; hg19: chr10-124273671; COSMIC: COSV64563219;