Genetic Variant NM_001273.5:c.2552C>A (chr12-6593191-G-T) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_001273.5(CHD4):c.2552C>A(p.Ser851Tyr) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

CHD4
NM_001273.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.57

Publications

6 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: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a domain Helicase ATP-binding (size 184) in uniprot entity CHD4_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_001273.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 12-6593191-G-T is Pathogenic according to our data. Variant chr12-6593191-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 266125.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD4	NM_001273.5 link	c.2552C>A	p.Ser851Tyr	missense_variant	Exon 17 of 40	ENST00000544040.7	NP_001264.2
CHD4	NM_001297553.2 link	c.2531C>A	p.Ser844Tyr	missense_variant	Exon 16 of 39		NP_001284482.1	Q14839F5GWX5
CHD4	NM_001363606.2 link	c.2513C>A	p.Ser838Tyr	missense_variant	Exon 17 of 40		NP_001350535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD4	ENST00000544040.7 link	c.2552C>A	p.Ser851Tyr	missense_variant	Exon 17 of 40	5	NM_001273.5	ENSP00000440542.2		Q14839-1
ENSG00000285238	ENST00000644480.2 link	n.2531C>A		non_coding_transcript_exon_variant	Exon 17 of 55			ENSP00000493629.2		A0A2R8Y445

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Sifrim-Hitz-Weiss syndrome

Pathogenic:1

Mar 14, 2025

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

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

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

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

PhyloP100

9.6

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.6

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

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0, 1.0, 1.0

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

Vest4

1.0

MutPred

0.88

.;.;.;Loss of MoRF binding (P = 0.2627);.;.;.;.;Loss of MoRF binding (P = 0.2627);.;Loss of MoRF binding (P = 0.2627);.;

MVP

0.98

MPC

3.3

ClinPred

0.99

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.99

Mutation Taster

=0/100

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over