chr12-6588320-C-A

Variant names:

• chr12-6588320-C-A
• rs886039919
• NM_001273.5:c.3443G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001273.5(CHD4):​c.3443G>T​(p.Trp1148Leu) 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 (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: 7.79
• Publications: 9 publications found

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), G2P, Ambry Genetics
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ENSG00000285238 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919
• PP5: Variant 12-6588320-C-A is Pathogenic according to our data. Variant chr12-6588320-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 266128.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001273.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD4	NM_001273.5	MANE Select	c.3443G>T	p.Trp1148Leu	missense	Exon 23 of 40	NP_001264.2	Q14839-1
	CHD4	NM_001297553.2		c.3422G>T	p.Trp1141Leu	missense	Exon 22 of 39	NP_001284482.1	F5GWX5
	CHD4	NM_001363606.2		c.3404G>T	p.Trp1135Leu	missense	Exon 23 of 40	NP_001350535.1	A0A2U3TZM0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD4	ENST00000544040.7	TSL:5 MANE Select	c.3443G>T	p.Trp1148Leu	missense	Exon 23 of 40	ENSP00000440542.2	Q14839-1
	CHD4	ENST00000357008.7	TSL:1	c.3404G>T	p.Trp1135Leu	missense	Exon 23 of 40	ENSP00000349508.3	A0A2U3TZM0
	ENSG00000285238	ENST00000644480.2		n.3422G>T		non_coding_transcript_exon	Exon 23 of 55	ENSP00000493629.2	A0A2R8Y445

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Sifrim-Hitz-Weiss syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.60
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.72		Gain of catalytic residue at W1148 (P = 0.0399)
MVP		0.93
MPC		2.5
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.78
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs886039919; hg19: chr12-6697486;