rs11538140
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
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
NM_002775.5 synonymous
Scores
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HTRA1 | NM_002775.5 | c.1221C>T | p.Asp407= | synonymous_variant | 8/9 | ENST00000368984.8 | NP_002766.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HTRA1 | ENST00000368984.8 | c.1221C>T | p.Asp407= | synonymous_variant | 8/9 | 1 | NM_002775.5 | ENSP00000357980 | P1 | |
HTRA1 | ENST00000648167.1 | c.903C>T | p.Asp301= | synonymous_variant | 8/9 | ENSP00000498033 | ||||
HTRA1 | ENST00000420892.1 | c.444C>T | p.Asp148= | synonymous_variant | 5/6 | 2 | ENSP00000412676 |
Frequencies
GnomAD3 genomes AF: 0.00312 AC: 474AN: 152118Hom.: 2 Cov.: 31
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GnomAD3 exomes AF: 0.00397 AC: 997AN: 251446Hom.: 3 AF XY: 0.00369 AC XY: 501AN XY: 135908
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GnomAD4 exome AF: 0.00346 AC: 5057AN: 1461714Hom.: 18 Cov.: 30 AF XY: 0.00333 AC XY: 2425AN XY: 727178
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GnomAD4 genome AF: 0.00311 AC: 473AN: 152236Hom.: 2 Cov.: 31 AF XY: 0.00320 AC XY: 238AN XY: 74430
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:5
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 04, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
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
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at