rs886039916

Variant names:

• chr12-6593191-G-T
• rs886039916
• NM_001273.5:c.2552C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

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. 12/21 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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.57

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]

ENSG00000285238 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• 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, 0.984
• 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. Variant chr12-6593191-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD4	NM_001273.5	c.2552C>A	p.Ser851Tyr	missense_variant	Exon 17 of 40	ENST00000544040.7	NP_001264.2
CHD4	NM_001297553.2	c.2531C>A	p.Ser844Tyr	missense_variant	Exon 16 of 39		NP_001284482.1
CHD4	NM_001363606.2	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	c.2552C>A	p.Ser851Tyr	missense_variant	Exon 17 of 40	5	NM_001273.5	ENSP00000440542.2
ENSG00000285238	ENST00000644480.2	n.2531C>A		non_coding_transcript_exon_variant	Exon 17 of 55			ENSP00000493629.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;T;.;D;.;.;.;.;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;.;.;H;.;.;.;.;H;.;.;.
PrimateAI	Pathogenic	0.90	D
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	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs886039916; hg19: chr12-6702357;