8-60838202-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017780.4(CHD7):c.4480C>T(p.Arg1494Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1494R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_017780.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHD7 | NM_017780.4 | c.4480C>T | p.Arg1494Ter | stop_gained | 19/38 | ENST00000423902.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHD7 | ENST00000423902.7 | c.4480C>T | p.Arg1494Ter | stop_gained | 19/38 | 5 | NM_017780.4 | P1 | |
CHD7 | ENST00000524602.5 | c.1717-24027C>T | intron_variant | 1 | |||||
CHD7 | ENST00000695853.1 | c.4480C>T | p.Arg1494Ter | stop_gained, NMD_transcript_variant | 19/37 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1450064Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 719886
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
CHARGE syndrome Pathogenic:4
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 12, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 158296). This premature translational stop signal has been observed in individuals with CHARGE syndrome (PMID: 16615981, 18089695, 21158681). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1494*) in the CHD7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHD7 are known to be pathogenic (PMID: 22461308, 25077900). - |
Pathogenic, no assertion criteria provided | research | Sbielas Lab-Department of Human Genetics University of Michigan, University of Michigan Medical School | Oct 27, 2017 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 18, 2017 | The p.R1494* pathogenic mutation (also known as c.4480C>T), located in coding exon 18 of the CHD7 gene, results from a C to T substitution at nucleotide position 4480. This changes the amino acid from an arginine to a stop codon within coding exon 18. This mutation has been identified in multiple individuals with a clinical diagnosis of CHARGE syndrome (Aramaki M et al. J. Pediatr., 2006 Mar;148:410-4; Asakura Y et al. J. Clin. Endocrinol. Metab., 2008 Mar;93:920-4; Fujita K et al. AJNR Am J Neuroradiol, 2009 Mar;30:629-34; Bartels CF et al. Genet Test Mol Biomarkers, 2010 Dec;14:881-91). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2018 | The R1494X nonsense variant in the CHD7 gene has been reported previously in association with CHARGE syndrome (Aramaki et al., 2006). The variant is not observed in large population cohorts (Lek et al., 2016). Approximately 45% of CHD7 pathogenic variants are nonsense changes predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay (Janssen et al., 2012; Zentner et al, 2010). In summary, we consider this variant to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at