NM_001235.5:c.580C>A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001235.5(SERPINH1):c.580C>A(p.Arg194Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00122 in 1,605,100 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001235.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SERPINH1 | NM_001235.5 | c.580C>A | p.Arg194Ser | missense_variant | Exon 2 of 5 | ENST00000358171.8 | NP_001226.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000959 AC: 146AN: 152254Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.000730 AC: 175AN: 239694Hom.: 0 AF XY: 0.000777 AC XY: 102AN XY: 131236
GnomAD4 exome AF: 0.00125 AC: 1815AN: 1452728Hom.: 2 Cov.: 70 AF XY: 0.00119 AC XY: 864AN XY: 723070
GnomAD4 genome AF: 0.000984 AC: 150AN: 152372Hom.: 0 Cov.: 34 AF XY: 0.000912 AC XY: 68AN XY: 74522
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
SERPINH1: BP4 -
Identified by noninvasive prenatal testing in a fetus with ultrasound findings suggestive of osteogenesis imperfecta; however, a second variant was not identified and confirmation via sequencing the child's genomic DNA after birth was not performed (PMID: 30043834); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30986427, 32161841, 30043834) -
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not specified Uncertain:1
Variant summary: SERPINH1 c.580C>A (p.Arg194Ser) results in a non-conservative amino acid change located in the Serpin domain (IPR023796) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00073 in 239694 control chromosomes. c.580C>A has been reported in the literature in individuals affected with low bone mass (Chen_2020). These reports do not provide unequivocal conclusions about association of the variant with Osteogenesis Imperfecta Type 10. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=4) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
SERPINH1-related disorder Uncertain:1
The SERPINH1 c.580C>A variant is predicted to result in the amino acid substitution p.Arg194Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Osteogenesis imperfecta type 10 Uncertain:1
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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Preterm premature rupture of membranes;C3151211:Osteogenesis imperfecta type 10 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at