rs372644599
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PP2PP3_ModerateBS2
The NM_017780.4(CHD7):c.5459G>A(p.Arg1820Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
CHD7
NM_017780.4 missense
NM_017780.4 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 10.0
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 Uncertain_significance. Variant got 1 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 6 uncertain in NM_017780.4
PP2
?
Missense variant where missense usually causes diseases, CHD7
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.858
BS2
?
High AC in GnomAdExome4 at 27 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHD7 | NM_017780.4 | c.5459G>A | p.Arg1820Gln | missense_variant | 26/38 | ENST00000423902.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHD7 | ENST00000423902.7 | c.5459G>A | p.Arg1820Gln | missense_variant | 26/38 | 5 | NM_017780.4 | P1 | |
CHD7 | ENST00000524602.5 | c.1717-11682G>A | intron_variant | 1 | |||||
CHD7 | ENST00000695853.1 | c.5459G>A | p.Arg1820Gln | missense_variant, NMD_transcript_variant | 26/37 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000283 AC: 7AN: 247722Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134392
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GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461122Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 726764
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74376
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 09, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 07, 2021 | Observed in a patient with idiopathic hypogonadotropic hypogonadism in published literature; patient was also heterozygous for variants in other genes (Zhao et al., 2019; Li et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 31689711, 28191889, 30576231) - |
CHARGE syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2022 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 411183). This missense change has been observed in individual(s) with CDH7-related conditions (PMID: 28191889, 31689711). This variant is present in population databases (rs372644599, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1820 of the CHD7 protein (p.Arg1820Gln). - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2019 | The p.R1820Q variant (also known as c.5459G>A), located in coding exon 25 of the CHD7 gene, results from a G to A substitution at nucleotide position 5459. The arginine at codon 1820 is replaced by glutamine, an amino acid with highly similar properties. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at