Variant 12-6591713-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong

The NM_001273.5(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 (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

CHD4
NM_001273.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.53

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a domain Helicase C-terminal (size 149) in uniprot entity CHD4_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001273.5

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CHD4. . Gene score misZ 6.3412 (greater than the threshold 3.09). Trascript score misZ 8.6114 (greater than threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, Sifrim-Hitz-Weiss syndrome.

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 id is 266124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6591713-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CHD4	NM_001273.5 linkuse as main transcript	c.3203G>A	p.Arg1068His	missense_variant	21/40	ENST00000544040.7	NP_001264.2
CHD4	NM_001297553.2 linkuse as main transcript	c.3182G>A	p.Arg1061His	missense_variant	20/39		NP_001284482.1
CHD4	NM_001363606.2 linkuse as main transcript	c.3164G>A	p.Arg1055His	missense_variant	21/40		NP_001350535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD4	ENST00000544040.7 linkuse as main transcript	c.3203G>A	p.Arg1068His	missense_variant	21/40	5	NM_001273.5	ENSP00000440542	A1	Q14839-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sifrim-Hitz-Weiss syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 15, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 12, 2021	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

.;T;.;D;.;.;.;.;.;.;.;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.91

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

3.6

.;.;.;H;.;.;.;.;H;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-4.7

.;D;.;.;.;.;.;.;.;.;.;.

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

.;D;.;.;.;.;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

.;D;.;.;.;.;.;.;.;.;.;.

Polyphen

1.0, 1.0

.;.;D;D;.;.;.;.;D;.;.;.

Vest4

0.95

MutPred

0.74

.;.;.;Loss of MoRF binding (P = 0.0092);.;.;.;.;Loss of MoRF binding (P = 0.0092);.;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

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over