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

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000083 ( 1 hom. )

Consequence

CHD7
NM_017780.4 missense

Scores

11
7
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 10.0
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000526 (8/152056) while in subpopulation SAS AF= 0.000207 (1/4820). AF 95% confidence interval is 0.0000376. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHD7NM_017780.4 linkc.2840G>A p.Arg947Gln missense_variant Exon 11 of 38 ENST00000423902.7 NP_060250.2 Q9P2D1-1Q6ZWF9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHD7ENST00000423902.7 linkc.2840G>A p.Arg947Gln missense_variant Exon 11 of 38 5 NM_017780.4 ENSP00000392028.1 Q9P2D1-1
CHD7ENST00000524602.5 linkc.1717-40201G>A intron_variant Intron 2 of 4 1 ENSP00000437061.1 Q9P2D1-4
CHD7ENST00000525508.1 linkc.2840G>A p.Arg947Gln missense_variant Exon 10 of 12 5 ENSP00000436027.1 Q9P2D1-2
CHD7ENST00000695853.1 linkn.2840G>A non_coding_transcript_exon_variant Exon 11 of 37 ENSP00000512218.1 A0A8Q3WKT9

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152056
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000763
AC:
19
AN:
248926
Hom.:
1
AF XY:
0.0000814
AC XY:
11
AN XY:
135074
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000580
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000886
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000828
AC:
121
AN:
1461532
Hom.:
1
Cov.:
32
AF XY:
0.0000880
AC XY:
64
AN XY:
727054
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000220
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000863
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152056
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74286
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.0000580
Hom.:
0
Bravo
AF:
0.0000416
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.000108
AC:
13
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

CHARGE syndrome;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia Uncertain:2
Mar 30, 2021
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1
Jul 06, 2016
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jan 25, 2021
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jan 08, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.87
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.84
D;.
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Uncertain
0.66
D;D
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Uncertain
2.8
M;M
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-3.5
D;D
REVEL
Pathogenic
0.71
Sift
Uncertain
0.010
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.56
MutPred
0.23
Loss of MoRF binding (P = 0.2372);Loss of MoRF binding (P = 0.2372);
MVP
0.97
MPC
0.53
ClinPred
0.83
D
GERP RS
5.5
Varity_R
0.42
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs768481542; hg19: chr8-61734587; API