rs2293870

chr10-122461760-G-Cchr10-122461760-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002775.5(HTRA1):c.108G>C(p.Gly36=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,101,636 control chromosomes in the GnomAD database, including 10,663 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. G36G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (1146 hom., cov: 32)
  • Exomes 𝑓: 0.14 (9517 hom.)
• Consequence: HTRA1 NM_002775.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -1.25

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 10-122461760-G-C is Benign according to our data. Variant chr10-122461760-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 21325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-122461760-G-C is described in Lovd as [Benign]. Variant chr10-122461760-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTRA1	NM_002775.5	c.108G>C	p.Gly36=	synonymous_variant	1/9	ENST00000368984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTRA1	ENST00000368984.8	c.108G>C	p.Gly36=	synonymous_variant	1/9	1	NM_002775.5	P1
HTRA1	ENST00000648167.1	c.154+3051G>C		intron_variant

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15298 AN: 147106 Hom.: 1146 Cov.: 32

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.000594

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.0545

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.112

GnomAD3 exomes AF: 0.0595 AC: 1060 AN: 17818 Hom.: 40 AF XY: 0.0579 AC XY: 630 AN XY: 10874

Gnomad AFR exome AF: 0.0245

Gnomad AMR exome AF: 0.0343

Gnomad ASJ exome AF: 0.0706

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0187

Gnomad FIN exome AF: 0.0918

Gnomad NFE exome AF: 0.0895

Gnomad OTH exome AF: 0.0761

GnomAD4 exome AF: 0.136 AC: 130142 AN: 954426 Hom.: 9517 Cov.: 32 AF XY: 0.135 AC XY: 61811 AN XY: 457794

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.0578

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.0000955

Gnomad4 SAS exome AF: 0.0305

Gnomad4 FIN exome AF: 0.122

Gnomad4 NFE exome AF: 0.147

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.104 AC: 15294 AN: 147210 Hom.: 1146 Cov.: 32 AF XY: 0.102 AC XY: 7301 AN XY: 71650

Gnomad4 AFR AF: 0.0261

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.000596

Gnomad4 SAS AF: 0.0295

Gnomad4 FIN AF: 0.164

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.111

Alfa AF: 0.0838 Hom.: 195

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 26310622, 18164066, 23478260) -

Macular degeneration Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

CARASIL syndrome Benign:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 01, 2017	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	10
Dann	Benign	0.83

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

Other links and lift over

dbSNP: rs2293870; hg19: chr10-124221276;