rs1064793083
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_017780.4(CHD7):c.3398C>T(p.Thr1133Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1133T) has been classified as Likely benign.
Frequency
Consequence
NM_017780.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHD7 | NM_017780.4 | c.3398C>T | p.Thr1133Met | missense_variant | 14/38 | ENST00000423902.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHD7 | ENST00000423902.7 | c.3398C>T | p.Thr1133Met | missense_variant | 14/38 | 5 | NM_017780.4 | P1 | |
CHD7 | ENST00000524602.5 | c.1717-33547C>T | intron_variant | 1 | |||||
CHD7 | ENST00000695853.1 | c.3398C>T | p.Thr1133Met | missense_variant, NMD_transcript_variant | 14/37 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 29, 2024 | The c.3398C>T (p.T1133M) alteration is located in coding exon 13 of the CHD7 gene. This alteration results from a C to T substitution at nucleotide position 3398, causing the threonine (T) at amino acid position 1133 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was detected as heterozygous in multiple individuals with features consistent with CHARGE syndrome, including two de novo occurrences (Ghaoui, 2015; O'Grady, 2016; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
CHARGE association;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 23, 2023 | Identified in one proband in large cohort of individuals with neurodevelopmental disorders in published literature; however, no further phenotypic information was provided (Stessman et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26436962, 26813943, 30653986, 28191889) - |
CHARGE association Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 16, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1133 of the CHD7 protein (p.Thr1133Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CHD7-related conditions (PMID: 26436962, 30653986). ClinVar contains an entry for this variant (Variation ID: 418124). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CHD7 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at