rs11538140

chr10-122512012-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002775.5(HTRA1):c.1221C>T(p.Asp407=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00343 in 1,613,950 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (18 hom.)
• Consequence: HTRA1 NM_002775.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.819

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 10-122512012-C-T is Benign according to our data. Variant chr10-122512012-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 299052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-122512012-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.819 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00311 (473/152236) while in subpopulation EAS AF= 0.0165 (85/5162). AF 95% confidence interval is 0.0136. There are 2 homozygotes in gnomad4. There are 238 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTRA1	NM_002775.5	c.1221C>T	p.Asp407=	synonymous_variant	8/9	ENST00000368984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTRA1	ENST00000368984.8	c.1221C>T	p.Asp407=	synonymous_variant	8/9	1	NM_002775.5	P1
HTRA1	ENST00000648167.1	c.903C>T	p.Asp301=	synonymous_variant	8/9
HTRA1	ENST00000420892.1	c.444C>T	p.Asp148=	synonymous_variant	5/6	2

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 474 AN: 152118 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00651

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00372

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00397 AC: 997 AN: 251446 Hom.: 3 AF XY: 0.00369 AC XY: 501 AN XY: 135908

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0146

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00721

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00346 AC: 5057 AN: 1461714 Hom.: 18 Cov.: 30 AF XY: 0.00333 AC XY: 2425 AN XY: 727178

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.0173

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00805

Gnomad4 NFE exome AF: 0.00320

Gnomad4 OTH exome AF: 0.00363

GnomAD4 genome AF: 0.00311 AC: 473 AN: 152236 Hom.: 2 Cov.: 31 AF XY: 0.00320 AC XY: 238 AN XY: 74430

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.0165

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00651

Gnomad4 NFE AF: 0.00372

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00411 Hom.: 4

Bravo AF: 0.00280

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00290

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 04, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Macular degeneration Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
Cadd	Benign	6.4
Dann	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11538140; hg19: chr10-124271528;