chr9-100300652-C-CA
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PVS1_ModerateBS1_SupportingBS2
The NM_014425.5(INVS):c.3182dupA(p.Asn1061fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,613,004 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00048 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000071 ( 2 hom. )
Consequence
INVS
NM_014425.5 frameshift
NM_014425.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.78
Genes affected
INVS (HGNC:17870): (inversin) This gene encodes a protein containing multiple ankyrin domains and two IQ calmodulin-binding domains. The encoded protein may function in renal tubular development and function, and in left-right axis determination. This protein interacts with nephrocystin and infers a connection between primary cilia function and left-right axis determination. A similar protein in mice interacts with calmodulin. Mutations in this gene have been associated with nephronophthisis type 2. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, May 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00469 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00048 (73/152188) while in subpopulation AFR AF= 0.00128 (53/41538). AF 95% confidence interval is 0.001. There are 1 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
INVS | NM_014425.5 | c.3182dupA | p.Asn1061fs | frameshift_variant | 17/17 | ENST00000262457.7 | NP_055240.2 | |
INVS | NM_001318381.2 | c.2894dupA | p.Asn965fs | frameshift_variant | 18/18 | NP_001305310.1 | ||
INVS | NM_001318382.2 | c.2204dupA | p.Asn735fs | frameshift_variant | 17/17 | NP_001305311.1 | ||
INVS | NR_134606.2 | n.3331dupA | non_coding_transcript_exon_variant | 17/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
INVS | ENST00000262457.7 | c.3182dupA | p.Asn1061fs | frameshift_variant | 17/17 | 1 | NM_014425.5 | ENSP00000262457.2 | ||
INVS | ENST00000262456.6 | c.2672dupA | p.Asn891fs | frameshift_variant | 18/18 | 5 | ENSP00000262456.2 |
Frequencies
GnomAD3 genomes AF: 0.000447 AC: 68AN: 152070Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000128 AC: 32AN: 250686Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135540
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GnomAD4 exome AF: 0.0000705 AC: 103AN: 1460816Hom.: 2 Cov.: 30 AF XY: 0.0000771 AC XY: 56AN XY: 726774
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GnomAD4 genome AF: 0.000480 AC: 73AN: 152188Hom.: 1 Cov.: 32 AF XY: 0.000443 AC XY: 33AN XY: 74412
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 31, 2023 | Variant summary: INVS c.3182dupA (p.Asn1061LysfsX20) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 0.00013 in 250686 control chromosomes. c.3182dupA has been reported in the literature in a patient with Bardet-Biedl syndrome and a patient with kidney and urinary tract abnormalities without evidence for causality (Nicolaou_2016 and Redin_2012). These reports do not provide unequivocal conclusions about association of the variant with Infantile Nephronophthisis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26489027, 22773737). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 15, 2018 | - - |
Infantile nephronophthisis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 20, 2022 | - - |
INVS-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 21, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Nephronophthisis Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at