10-122461760-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>T(p.Gly36=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 1,102,096 control chromosomes in the GnomAD database, including 29,815 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 0.23 (4202 hom., cov: 32)
  • Exomes 𝑓: 0.23 (25613 hom.)
• Consequence: HTRA1 NM_002775.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 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=-0.71).
• BP6: Variant 10-122461760-G-T is Benign according to our data. Variant chr10-122461760-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 21326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-122461760-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.233 AC: 34326 AN: 147104 Hom.: 4193 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.170

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.235

GnomAD3 exomes AF: 0.321 AC: 5727 AN: 17818 Hom.: 986 AF XY: 0.326 AC XY: 3540 AN XY: 10874

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.337

Gnomad ASJ exome AF: 0.299

Gnomad EAS exome AF: 0.487

Gnomad SAS exome AF: 0.391

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.279

GnomAD4 exome AF: 0.227 AC: 216639 AN: 954890 Hom.: 25613 Cov.: 32 AF XY: 0.229 AC XY: 104757 AN XY: 458050

Gnomad4 AFR exome AF: 0.245

Gnomad4 AMR exome AF: 0.327

Gnomad4 ASJ exome AF: 0.238

Gnomad4 EAS exome AF: 0.426

Gnomad4 SAS exome AF: 0.348

Gnomad4 FIN exome AF: 0.302

Gnomad4 NFE exome AF: 0.217

Gnomad4 OTH exome AF: 0.249

GnomAD4 genome AF: 0.233 AC: 34371 AN: 147206 Hom.: 4202 Cov.: 32 AF XY: 0.236 AC XY: 16911 AN XY: 71646

Gnomad4 AFR AF: 0.234

Gnomad4 AMR AF: 0.229

Gnomad4 ASJ AF: 0.210

Gnomad4 EAS AF: 0.421

Gnomad4 SAS AF: 0.313

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.216

Gnomad4 OTH AF: 0.232

Alfa AF: 0.135 Hom.: 195

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	10
Dann	Benign	0.93

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; COSMIC: COSV64563702; COSMIC: COSV64563702;