rs121434338
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_017780.4(CHD7):c.3082A>G(p.Ile1028Val) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
CHD7
NM_017780.4 missense
NM_017780.4 missense
Scores
8
6
5
Clinical Significance
Conservation
PhyloP100: 9.32
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 15 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_017780.4
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, CHD7
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 8-60822627-A-G is Pathogenic according to our data. Variant chr8-60822627-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60822627-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHD7 | NM_017780.4 | c.3082A>G | p.Ile1028Val | missense_variant | 12/38 | ENST00000423902.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHD7 | ENST00000423902.7 | c.3082A>G | p.Ile1028Val | missense_variant | 12/38 | 5 | NM_017780.4 | P1 | |
CHD7 | ENST00000524602.5 | c.1717-39602A>G | intron_variant | 1 | |||||
CHD7 | ENST00000525508.1 | c.3082A>G | p.Ile1028Val | missense_variant | 11/12 | 5 | |||
CHD7 | ENST00000695853.1 | c.3082A>G | p.Ile1028Val | missense_variant, NMD_transcript_variant | 12/37 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
CHARGE syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, University of Torino | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2022 | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 2022). This missense change has been observed in individual(s) with CHARGE syndrome (PMID: 15300250, 16155193, 18073582, 20884005, 21158681, 22539353). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1028 of the CHD7 protein (p.Ile1028Val). Experimental studies have shown that this missense change affects CHD7 function (PMID: 25472840). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 27, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2023 | Published functional studies demonstrate a damaging effect; the I1028V variant causes a complete loss of function of CHD7 (Balasubramanian et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20884005, 16155193, 18073582, 25472840, 15300250, 22539353, 26563674, 22461308, 28475860, 21158681, 32914532, 34828433, 33189935) - |
Hypogonadotropic hypogonadism Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | May 31, 2022 | ACMG categories: PS1,PS4,PM2,PM5 - |
CHARGE syndrome;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
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
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
N;N
MutationTaster
Benign
A;A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Benign
D;D
Sift4G
Uncertain
D;D
Polyphen
P;P
Vest4
MutPred
Loss of catalytic residue at I1028 (P = 0.0656);Loss of catalytic residue at I1028 (P = 0.0656);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at