chr10-122488726-C-G

Variant names:

• chr10-122488726-C-G
• rs12267142
• NM_002775.5:c.473-176C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002775.5(HTRA1):​c.473-176C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0463 in 152,290 control chromosomes in the GnomAD database, including 235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.046 (235 hom., cov: 32)
• Consequence: HTRA1 NM_002775.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.70
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 10-122488726-C-G is Benign according to our data. Variant chr10-122488726-C-G is described in ClinVar as Benign. ClinVar VariationId is 1263788.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.473-176C>G		intron_variant	Intron 1 of 8	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.473-176C>G		intron_variant	Intron 1 of 8	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.155-176C>G		intron_variant	Intron 1 of 8			ENSP00000498033.1

Frequencies

GnomAD3 genomes AF: 0.0464 AC: 7057 AN: 152172 Hom.: 234 Cov.: 32

Gnomad AFR AF: 0.0168

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0472

Gnomad ASJ AF: 0.0677

Gnomad EAS AF: 0.0672

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0648

Gnomad OTH AF: 0.0621

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

GnomAD4 genome AF: 0.0463 AC: 7056 AN: 152290 Hom.: 235 Cov.: 32 AF XY: 0.0440 AC XY: 3280 AN XY: 74468

African (AFR) AF: 0.0168 AC: 699 AN: 41572

American (AMR) AF: 0.0471 AC: 721 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0677 AC: 235 AN: 3470

East Asian (EAS) AF: 0.0672 AC: 348 AN: 5178

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4822

European-Finnish (FIN) AF: 0.0364 AC: 386 AN: 10612

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0648 AC: 4406 AN: 68012

Other (OTH) AF: 0.0614 AC: 130 AN: 2116

Alfa AF: 0.0224 Hom.: 12

Bravo AF: 0.0478

Asia WGS AF: 0.0350 AC: 123 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.050
DANN	Benign	0.46
PhyloP100		-1.7
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: rs12267142; hg19: chr10-124248242;