Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The ENST00000544040.7(CHD4):c.3203G>A(p.Arg1068His) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1068S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CHD4
ENST00000544040.7 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.53

Publications

11 publications found

Variant links:

Genes affected

CHD4 (HGNC:1919): (chromodomain helicase DNA binding protein 4) The product of this gene belongs to the SNF2/RAD54 helicase family. It represents the main component of the nucleosome remodeling and deacetylase complex and plays an important role in epigenetic transcriptional repression. Patients with dermatomyositis develop antibodies against this protein. Somatic mutations in this gene are associated with serous endometrial tumors. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2014]

CHD4 Gene-Disease associations (from GenCC):

Sifrim-Hitz-Weiss syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

CHD4 links:

ENSG00000285238 (HGNC:):

ENSG00000285238 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 chr12-6591714-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2633887.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.913

PP5

Variant 12-6591713-C-T is Pathogenic according to our data. Variant chr12-6591713-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 266124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000544040.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHD4	NM_001273.5	MANE Select	c.3203G>A	p.Arg1068His	missense	Exon 21 of 40	NP_001264.2
CHD4	NM_001297553.2		c.3182G>A	p.Arg1061His	missense	Exon 20 of 39	NP_001284482.1
CHD4	NM_001363606.2		c.3164G>A	p.Arg1055His	missense	Exon 21 of 40	NP_001350535.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHD4	ENST00000544040.7	TSL:5 MANE Select	c.3203G>A	p.Arg1068His	missense	Exon 21 of 40	ENSP00000440542.2
CHD4	ENST00000357008.7	TSL:1	c.3164G>A	p.Arg1055His	missense	Exon 21 of 40	ENSP00000349508.3
ENSG00000285238	ENST00000644480.2		n.3182G>A		non_coding_transcript_exon	Exon 21 of 55	ENSP00000493629.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Sifrim-Hitz-Weiss syndrome (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

3.6

PhyloP100

7.5

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.74

Loss of MoRF binding (P = 0.0092)

MVP

0.97

MPC

3.1

ClinPred

1.0

GERP RS

5.2

Varity_R

0.79

gMVP

0.97

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.26

Position offset: 10

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

Publications

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rs886039915

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over