10-122506792-C-T

Position:

chr10-122506792-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_002775.5(HTRA1):c.879C>T(p.Thr293=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 1,613,890 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T293T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 17 hom. )

Consequence

HTRA1
NM_002775.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.00700

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 10-122506792-C-T is Benign according to our data. Variant chr10-122506792-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 299051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-122506792-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.007 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00278 (423/152196) while in subpopulation NFE AF= 0.00474 (322/67998). AF 95% confidence interval is 0.00431. There are 1 homozygotes in gnomad4. There are 183 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTRA1	NM_002775.5 linkuse as main transcript	c.879C>T	p.Thr293=	synonymous_variant	4/9	ENST00000368984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HTRA1	ENST00000368984.8 linkuse as main transcript	c.879C>T	p.Thr293=	synonymous_variant	4/9	1	NM_002775.5	P1
HTRA1	ENST00000648167.1 linkuse as main transcript	c.561C>T	p.Thr187=	synonymous_variant	4/9
HTRA1	ENST00000420892.1 linkuse as main transcript	c.102C>T	p.Thr34=	synonymous_variant	1/6	2

Frequencies

GnomAD3 genomes

AF:

0.00278

AC:

423

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00473

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00265

AC:

667

AN:

251268

Hom.:

AF XY:

0.00247

AC XY:

335

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00176

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000511

Gnomad NFE exome

AF:

0.00469

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00449

AC:

6564

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00427

AC XY:

3102

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00219

Gnomad4 ASJ exome

AF:

0.00191

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.000901

Gnomad4 NFE exome

AF:

0.00544

Gnomad4 OTH exome

AF:

0.00459

GnomAD4 genome

AF:

0.00278

AC:

423

AN:

152196

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

183

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000963

Gnomad4 AMR

AF:

0.00307

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00474

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00280

Hom.:

Bravo

AF:

0.00326

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00453

EpiControl

AF:

0.00391

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	HTRA1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 19, 2020

- -

Macular degeneration

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.81

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over