NM_002775.5:c.972+99C>T

Variant names:

• chr10-122506984-C-T
• rs2672582
• NM_002775.5:c.972+99C>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.972+99C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,084,920 control chromosomes in the GnomAD database, including 60,484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7113 hom., cov: 32)
  • Exomes 𝑓: 0.33 (53371 hom.)
• Consequence: HTRA1 NM_002775.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.133
• Publications: 4 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: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 10-122506984-C-T is Benign according to our data. Variant chr10-122506984-C-T is described in ClinVar as Benign. ClinVar VariationId is 1233351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.972+99C>T		intron_variant	Intron 4 of 8	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.972+99C>T		intron_variant	Intron 4 of 8	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.654+99C>T		intron_variant	Intron 4 of 8			ENSP00000498033.1
HTRA1	ENST00000420892.1	c.195+99C>T		intron_variant	Intron 1 of 5	2		ENSP00000412676.1

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44204 AN: 151800 Hom.: 7103 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.297

GnomAD4 exome AF: 0.332 AC: 309419 AN: 933002 Hom.: 53371 AF XY: 0.329 AC XY: 157766 AN XY: 479916

African (AFR) AF: 0.165 AC: 3828 AN: 23180

American (AMR) AF: 0.510 AC: 18427 AN: 36162

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 6790 AN: 22378

East Asian (EAS) AF: 0.377 AC: 13031 AN: 34552

South Asian (SAS) AF: 0.300 AC: 21282 AN: 70944

European-Finnish (FIN) AF: 0.322 AC: 11806 AN: 36688

Middle Eastern (MID) AF: 0.244 AC: 935 AN: 3830

European-Non Finnish (NFE) AF: 0.332 AC: 219633 AN: 662208

Other (OTH) AF: 0.318 AC: 13687 AN: 43060

GnomAD4 genome AF: 0.291 AC: 44234 AN: 151918 Hom.: 7113 Cov.: 32 AF XY: 0.293 AC XY: 21771 AN XY: 74226

African (AFR) AF: 0.171 AC: 7080 AN: 41408

American (AMR) AF: 0.409 AC: 6249 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1020 AN: 3468

East Asian (EAS) AF: 0.384 AC: 1968 AN: 5130

South Asian (SAS) AF: 0.300 AC: 1448 AN: 4820

European-Finnish (FIN) AF: 0.322 AC: 3396 AN: 10556

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22294 AN: 67952

Other (OTH) AF: 0.294 AC: 620 AN: 2106

Alfa AF: 0.305 Hom.: 11320

Bravo AF: 0.295

Asia WGS AF: 0.357 AC: 1237 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Nov 12, 2018

GeneDx

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	-0.93
CADD	Benign	2.2
DANN	Benign	0.63
PhyloP100		-0.13
PromoterAI		-0.020	Neutral
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: rs2672582; hg19: chr10-124266500; COSMIC: COSV64564677;