rs1555612459

Positions:

• chr17-7902985-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The ENST00000330494.12(CHD3):​c.3419G>A​(p.Gly1140Asp) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHD3 ENST00000330494.12 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

CHD3 (HGNC:1918): (chromodomain helicase DNA binding protein 3) This gene encodes a member of the CHD family of proteins which are characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. This protein is one of the components of a histone deacetylase complex referred to as the Mi-2/NuRD complex which participates in the remodeling of chromatin by deacetylating histones. Chromatin remodeling is essential for many processes including transcription. Autoantibodies against this protein are found in a subset of patients with dermatomyositis. Three alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain Helicase C-terminal (size 165) in uniprot entity CHD3_HUMAN there are 44 pathogenic changes around while only 0 benign (100%) in ENST00000330494.12
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CHD3. . Gene score misZ 6.1518 (greater than the threshold 3.09). Trascript score misZ 8.4103 (greater than threshold 3.09). GenCC has associacion of gene with Snijders Blok-Campeau syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD3	NM_001005273.3	c.3419G>A	p.Gly1140Asp	missense_variant	22/40	ENST00000330494.12	NP_001005273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD3	ENST00000330494.12	c.3419G>A	p.Gly1140Asp	missense_variant	22/40	1	NM_001005273.3	ENSP00000332628	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2019

The alteration results in an amino acid change:_x000D_ _x000D_ The c.3596G>A (p.G1199D) alteration is located in coding exon 22 of the CHD3 gene. This alteration results from a G to A substitution at nucleotide position 3596, causing the glycine (G) at amino acid position 1199 to be replaced by an aspartic acid (D). The alteration is not observed in healthy cohorts:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the CHD3 c.3596G>A alteration was not observed, with coverage at this position. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.G1199 amino acid is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ _x000D_ The p.G1199 amino acid is part of the highly conserved helicase “STRAGGLG” motif called motif V, which is located in the helicase/ATPase domain of CHD3 and found to play an important role in coupling ATP hydrolysis to the chromatin remodeling function of proteins belonging to the different subfamilies of chromatin modifiers (Smith, 2005). Deletion of this 8-residue motif within the SWI/SNF ATPase domain did not interfere with the DNA-dependent ATP hydrolysis function of the protein but severely reduced duplex unwinding and nucleosome sliding activity required for chromatin remodeling, thus resulting in a null phenotype in vivo in yeast (Smith, 2005). However, single nucleotide substitutions at two of the residues within this motif had less severe effects on the function of the protein as compared to deletion of the entire motif (Richmond, 1996). The alteration is predicted deleterious by in silico models:_x000D_ _x000D_ The p.G1199D alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	.;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.8	.;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.5	D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.96
MutPred		0.93		.;Loss of methylation at R1137 (P = 0.0491);Loss of methylation at R1137 (P = 0.0491);
MVP		0.92
MPC		3.1
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.82
gMVP		1.0

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

Other links and lift over

dbSNP: rs1555612459; hg19: chr17-7806303;