rs1555611722

Positions:

• chr17-7900706-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_001005273.3(CHD3):​c.2953C>T​(p.Arg985Trp) variant causes a missense change involving the alteration of a non-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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R985Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHD3 NM_001005273.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.25

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7900707-G-A is described in Lovd as [Pathogenic].
• 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, 0.839
• PP5: Variant 17-7900706-C-T is Pathogenic according to our data. Variant chr17-7900706-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7900706-C-T is described in Lovd as [Pathogenic]. Variant chr17-7900706-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD3	NM_001005273.3	c.2953C>T	p.Arg985Trp	missense_variant	18/40	ENST00000330494.12	NP_001005273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD3	ENST00000330494.12	c.2953C>T	p.Arg985Trp	missense_variant	18/40	1	NM_001005273.3	ENSP00000332628	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Snijders Blok-Campeau syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Aug 31, 2022	PM2, PM5, PP2, PP3, PP5 -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 12, 2023	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Feb 19, 2019	This variant is interpreted as a Pathogenic for Snijders Blok-Campeau syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PM2 : Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6-Strong :PM6 upgraded in strength to Strong due to multiple de novo occurrences (PMID:30397230). PM1-supporting : PM1 downgraded in strength to Supporting. PP2 : Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease. PS4-Moderate : PS4 downgraded in strength to Moderate. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2019

The alteration results in an amino acid change:_x000D_ _x000D_ The c.3130C>T (p.R1044W) alteration is located in coding exon 18 of the CHD3 gene. This alteration results from a C to T substitution at nucleotide position 3130, causing the arginine (R) at amino acid position 1044 to be replaced by a tryptophan (W). The alteration is not observed in healthy cohorts:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the CHD3 c.3130C>T alteration was not observed, with coverage at this position. Based on data from the NHLBI Exome Sequencing Project (ESP), the CHD3 c.3130C>T alteration was not observed among 6,503 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. The amino acid change has been observed in affected individuals: _x000D_ _x000D_ This alteration has been reported once from a cohort of individuals with developmental disorders (DDD, 2017)._x000D_ _x000D_ Deciphering Developmental Disorders Study. Nature. (2017) 542(7642). PMID:28135719. Supplemental 1 The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.R1044 amino acid is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ _x000D_ The p.R1044W amino acid is located in the SNF2-like ATPase/helicase domain, which consists of two subdomains; a helicase ATP-binding lobe and C-terminal lobe. The majority of mutations have been observed to cluster within or around this domain. This domain uses ATPase activity to provide energy for nucleosome remodeling (Snijders Blok, 2018). The alteration is predicted deleterious by in silico models:_x000D_ _x000D_ The p.R1044W alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics laboratory, Necker Hospital

Jan 14, 2021

- -

Intellectual disability Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

CHU Sainte-Justine Research Center, University of Montreal

May 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	.;.;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	-0.075	T
MutationAssessor	Benign	1.4	.;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.6	D;D;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.74
MutPred		0.73		.;Loss of MoRF binding (P = 0.0708);Loss of MoRF binding (P = 0.0708);
MVP		0.81
MPC		2.6
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.68
gMVP		0.81

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: rs1555611722; hg19: chr17-7804024;