rs398124321
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_017780.4(CHD7):c.5405-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
CHD7
NM_017780.4 splice_region, intron
NM_017780.4 splice_region, intron
Scores
2
Splicing: ADA: 0.9358
1
Clinical Significance
Conservation
PhyloP100: 0.922
Genes affected
CHD7 (HGNC:20626): (chromodomain helicase DNA binding protein 7) This gene encodes a protein that contains several helicase family domains. Mutations in this gene have been found in some patients with the CHARGE syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-60850486-G-A is Pathogenic according to our data. Variant chr8-60850486-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 95795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60850486-G-A is described in Lovd as [Pathogenic]. Variant chr8-60850486-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CHD7 | ENST00000423902.7 | c.5405-7G>A | splice_region_variant, intron_variant | 5 | NM_017780.4 | ENSP00000392028.1 | ||||
| CHD7 | ENST00000524602.5 | c.1717-11743G>A | intron_variant | 1 | ENSP00000437061.1 | |||||
| CHD7 | ENST00000695853.1 | n.5405-7G>A | splice_region_variant, intron_variant | ENSP00000512218.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000207 AC: 3AN: 1449966Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 718616
GnomAD4 exome
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3
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1449966
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31
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0
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718616
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:19
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
CHARGE syndrome Pathogenic:11
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21931733). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.98). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 15300250 , 22033296 ) and observed in multiple (>3) similarly affected unrelated individuals (PMID: 16155193 , 16615981 , 21158681 , 21931733). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000095795). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Sep 08, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 11, 2018 | Variant summary: CHD7 c.5405-7G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. One computational tool predicts that the variant creates a cryptic 3 acceptor site. Two independent mini-gene assays confirm the impact on splicing, specificaly the introduction of a 5-bp intronic sequence by activation of a cryptic acceptor site leading to a frameshift mutation (Legendre_2018, Song_2011). The variant was absent in 275496 control chromosomes (gnomAD). The variant, c.5405-7G>A, has been reported in the literature in multiple individuals affected with CHARGE Syndrome (Vissers_2004, Bilan_2012, Janssen_2012, Song_2011, Legendre_2018). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 05, 2024 | This sequence change falls in intron 25 of the CHD7 gene. It does not directly change the encoded amino acid sequence of the CHD7 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with CHARGE syndrome (PMID: 15300250, 16155193, 16615981, 21158681, 21931733, 22033296). In at least one individual the variant was observed to be de novo. This variant is also known as IVS25-7G>A and IVS26-7G>A. ClinVar contains an entry for this variant (Variation ID: 95795). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21931733). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Jan 14, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Dec 20, 2016 | ACMG categories: PS2,PS3,PM2,PP3,PP4,PP5 - |
| Pathogenic, criteria provided, single submitter | in vitro | Laboratoire de Genetique Biologique, CHU de Poitiers | May 05, 2017 | found de novo on several CHARGE syndrome patients. Minigene assays confirm the use of a new acceptor splice site leading to frameshift in exon 26 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Sep 05, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea | - | - - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 16, 2022 | Published in vitro splicing assay and RT-PCR studies indicate this variant creates a new splice acceptor site in intron 25 that results in abnormal gene splicing resulting in a frameshift in the resultant product (Song et al., 2011; Legendre et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 30216942, 30587507, 31130284, 21931733, 21158681, 16155193, 29255276, 22033296, 15300250, 32763379, 34008892, 32969205, 16615981) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Feb 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 12, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2019 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 16, 2016 | The c.5405-7G>A intronic pathogenic mutation results from a G to A substitution 7 nucleotides upstream from coding exon 25 in the CHD7 gene. This mutation has been reported in multiple individuals with a clinical diagnosis of CHARGE syndrome, including one de novo occurrence (Vissers LE, et al. Nat. Genet. 2004 Sep; 36(9):955-7; Jongmans MC, et al. J. Med. Genet. 2006 Apr; 43(4):306-14; Aramaki M, et al. J. Pediatr. 2006 Mar; 148(3):410-4; Song MH, et al. PLoS ONE. 2011; 6(9):e24511). In addition, an in vitro splicing analysis demonstrated the introduction of 5 additional nucleotides due to the activation of a cryptic acceptor site (Song MH, et al. PLoS ONE. 2011; 6(9):e24511). Based on the supporting evidence, c.5405-7G>A is interpreted as a disease-causing mutation. - |
CHD7-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 16, 2023 | The CHD7 c.5405-7G>A variant is predicted to interfere with splicing. This is a well-documented recurrent pathogenic variant causative for CHARGE syndrome and has previously been reported as de novo (Bilan et al. 2012. PubMed ID: 22033296; Song et al. 2011. PubMed ID: 21931733). Functional studies found it creates a frameshift and premature protein termination by activating a cryptic splice acceptor site and introducing a five-base pair intronic sequence to the CHD7 messenger RNA (Song et al. 2011. PubMed ID: 21931733; Legendre et al. 2018. PubMed ID: 29255276). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Hypogonadotropic hypogonadism 5 with or without anosmia Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The heterozygous c.5405-7G>A variant in CHD7 was identified by our study in one individual with hypogonadotropic hypogonadism with or without anosmia. Trio exome analysis showed this variant to be de novo and there are multiple reports of de novo inheritance in the literature (PMID: 15300250, 22033296). This variant was absent from large population studies and has been reported in ClinVar (Variation ID: 95795). In vitro functional studies provide some evidence that the c.5405-7G>A variant may impact protein function by causing a five base pair insertion during in vitro splicing (PMID: 21931733). However, these types of assays may not accurately represent biological function. In summary, the c.5405-7G>A variant is pathogenic based off of our findings and multiple de novo reports in the literature. ACMG/AMP Criteria applied: PM2, PS2, PM6_Strong, PS3_Moderate (Richards 2015). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 2
DS_AL_spliceai
Position offset: 7
Find out detailed SpliceAI scores and Pangolin per-transcript scores at