chr8-60822028-G-A
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_017780.4(CHD7):c.2840G>A(p.Arg947Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,588 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_017780.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHD7 | ENST00000423902.7 | c.2840G>A | p.Arg947Gln | missense_variant | Exon 11 of 38 | 5 | NM_017780.4 | ENSP00000392028.1 | ||
CHD7 | ENST00000524602.5 | c.1717-40201G>A | intron_variant | Intron 2 of 4 | 1 | ENSP00000437061.1 | ||||
CHD7 | ENST00000525508.1 | c.2840G>A | p.Arg947Gln | missense_variant | Exon 10 of 12 | 5 | ENSP00000436027.1 | |||
CHD7 | ENST00000695853.1 | n.2840G>A | non_coding_transcript_exon_variant | Exon 11 of 37 | ENSP00000512218.1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152056Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000763 AC: 19AN: 248926Hom.: 1 AF XY: 0.0000814 AC XY: 11AN XY: 135074
GnomAD4 exome AF: 0.0000828 AC: 121AN: 1461532Hom.: 1 Cov.: 32 AF XY: 0.0000880 AC XY: 64AN XY: 727054
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152056Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74286
ClinVar
Submissions by phenotype
CHARGE syndrome;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia Uncertain:2
CHD7 NM_017780.3 exon11 p.Arg947Gln (c.2840G>A): This variant has been reported in the literature in 1 individual with a clinical suspicion of CHARGE syndrome (Bartels 2010 PMID:21158661). This variant is present in 0.02% (7/30590) of South Asian alleles including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/8-61734587-G-A). This variant is present in ClinVar (Variation ID:529140). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
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Inborn genetic diseases Uncertain:1
The p.R947Q variant (also known as c.2840G>A), located in coding exon 10 of the CHD7 gene, results from a G to A substitution at nucleotide position 2840. The arginine at codon 947 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected in an individual undergoing CHD7 analysis; however, no phenotypic information was provided (Bartels CF et al. Genet Test Mol Biomarkers, 2010GTF;14:881-91). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5914 samples (11828 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Previously reported as a variant of uncertain significance in a patient with CHARGE syndrome (Bartels et al., 2010); This variant is associated with the following publications: (PMID: 33206719, 22539353, 21158681) -
CHARGE syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at