rs1312886444

Variant names:

• chr10-122461679-C-G
• rs1312886444
• NM_002775.5:c.27C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_002775.5(HTRA1):​c.27C>G​(p.Leu9Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000304 in 1,314,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: HTRA1 NM_002775.5 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.521
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 10-122461679-C-G is Benign according to our data. Variant chr10-122461679-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3046807.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.521 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTRA1	NM_002775.5	c.27C>G	p.Leu9Leu	synonymous_variant	Exon 1 of 9	ENST00000368984.8	NP_002766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTRA1	ENST00000368984.8	c.27C>G	p.Leu9Leu	synonymous_variant	Exon 1 of 9	1	NM_002775.5	ENSP00000357980.3
HTRA1	ENST00000648167.1	c.154+2970C>G		intron_variant	Intron 1 of 8			ENSP00000498033.1

Frequencies

GnomAD3 genomes AF: 0.0000203 AC: 3 AN: 147748 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000453

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.57e-7 AC: 1 AN: 1167100 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 575050

African (AFR) AF: 0.00 AC: 0 AN: 22124

American (AMR) AF: 0.00 AC: 0 AN: 22026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16868

East Asian (EAS) AF: 0.00 AC: 0 AN: 16662

South Asian (SAS) AF: 0.00 AC: 0 AN: 68876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3070

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 950938

Other (OTH) AF: 0.00 AC: 0 AN: 44058

GnomAD4 genome AF: 0.0000203 AC: 3 AN: 147748 Hom.: 0 Cov.: 32 AF XY: 0.0000278 AC XY: 2 AN XY: 71874

African (AFR) AF: 0.00 AC: 0 AN: 41050

American (AMR) AF: 0.00 AC: 0 AN: 14876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000453 AC: 3 AN: 66216

Other (OTH) AF: 0.00 AC: 0 AN: 2030

Alfa AF: 0.000132 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

HTRA1-related disorder Benign:1

Jun 16, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.0
DANN	Benign	0.45
PhyloP100		-0.52
PromoterAI		0.00040	Neutral

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: rs1312886444; hg19: chr10-124221195;