Genetic Variant NM_001005273.3:c.2953C>T (chr17-7900706-C-T) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_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. R985P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

CHD3
NM_001005273.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 1.25

Publications

1 publications found

Variant links:

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]

CHD3 Gene-Disease associations (from GenCC):

Snijders Blok-Campeau syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Illumina

CHD3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 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-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2507027.Status of the report is no_assertion_criteria_provided, 0 stars.

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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 520977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005273.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHD3	NM_001005273.3	MANE Select	c.2953C>T	p.Arg985Trp	missense	Exon 18 of 40	NP_001005273.1	Q12873-1
CHD3	NM_001437504.1		c.3130C>T	p.Arg1044Trp	missense	Exon 18 of 40	NP_001424433.1	A0A8V8TR54
CHD3	NM_001005271.3		c.3130C>T	p.Arg1044Trp	missense	Exon 18 of 40	NP_001005271.2	Q12873-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHD3	ENST00000330494.12	TSL:1 MANE Select	c.2953C>T	p.Arg985Trp	missense	Exon 18 of 40	ENSP00000332628.7	Q12873-1
CHD3	ENST00000358181.8	TSL:1	c.2953C>T	p.Arg985Trp	missense	Exon 18 of 39	ENSP00000350907.4	Q12873-2
CHD3	ENST00000700753.1		c.3130C>T	p.Arg1044Trp	missense	Exon 18 of 40	ENSP00000515165.1	A0A8V8TR54

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Snijders Blok-Campeau syndrome (5)

Inborn genetic diseases (1)

Intellectual disability (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

-0.075

MutationAssessor

Benign

1.4

PhyloP100

1.3

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-7.6

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.74

MutPred

0.73

Loss of MoRF binding (P = 0.0708)

MVP

0.81

MPC

2.6

ClinPred

1.0

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.68

gMVP

0.81

Mutation Taster

=18/82

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over