Genetic Variant NM_001273.5:c.3203G>A (chr12-6591713-C-T) – ACMG Classification: Pathogenic (15 pts)

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:

ENSG00000285238 (HGNC:):

ENSG00000285238 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 the CHD4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 33 curated benign missense variants. Gene score misZ: 6.3412 (above the threshold of 3.09). Trascript score misZ: 8.6114 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
CHD4	NM_001273.5 link	c.3203G>A	p.Arg1068His	missense_variant	Exon 21 of 40	ENST00000544040.7	NP_001264.2
CHD4	NM_001297553.2 link	c.3182G>A	p.Arg1061His	missense_variant	Exon 20 of 39		NP_001284482.1	Q14839F5GWX5
CHD4	NM_001363606.2 link	c.3164G>A	p.Arg1055His	missense_variant	Exon 21 of 40		NP_001350535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD4	ENST00000544040.7 link	c.3203G>A	p.Arg1068His	missense_variant	Exon 21 of 40	5	NM_001273.5	ENSP00000440542.2		Q14839-1
ENSG00000285238	ENST00000644480.2 link	n.3182G>A		non_coding_transcript_exon_variant	Exon 21 of 55			ENSP00000493629.2		A0A2R8Y445

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

Mar 15, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2025

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases

Pathogenic:1

Oct 05, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.;.;.

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