rs886039918

Variant names:

• chr12-6587897-C-A
• rs886039918
• NM_001273.5:c.3518G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-6587897-C-A
• chr12-6587897-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001273.5(CHD4):​c.3518G>T​(p.Arg1173Leu) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1173W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD4 NM_001273.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.87
• Publications: 7 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), Ambry Genetics, G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ENSG00000285238 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001273.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-6587898-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1030325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 12-6587897-C-A is Pathogenic according to our data. Variant chr12-6587897-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 266127.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	c.3518G>T	p.Arg1173Leu	missense_variant	Exon 24 of 40	ENST00000544040.7	NP_001264.2
CHD4	NM_001297553.2	c.3497G>T	p.Arg1166Leu	missense_variant	Exon 23 of 39		NP_001284482.1
CHD4	NM_001363606.2	c.3479G>T	p.Arg1160Leu	missense_variant	Exon 24 of 40		NP_001350535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD4	ENST00000544040.7	c.3518G>T	p.Arg1173Leu	missense_variant	Exon 24 of 40	5	NM_001273.5	ENSP00000440542.2
ENSG00000285238	ENST00000644480.2	n.3497G>T		non_coding_transcript_exon_variant	Exon 24 of 55			ENSP00000493629.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Aug 20, 2018

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	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T;.;D;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	.;.;.;H;.;.;.;.;H;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.3	.;D;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	.;D;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.
Polyphen		0.87, 0.19, 0.57	.;.;P;B;.;.;.;.;P;.;.;.
Vest4		0.95
MutPred		0.71		.;.;.;Loss of MoRF binding (P = 0.011);.;.;.;.;Loss of MoRF binding (P = 0.011);.;Loss of MoRF binding (P = 0.011);.;
MVP		0.98
MPC		1.9
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.68
gMVP		1.0
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: -21

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

Other links and lift over

dbSNP: rs886039918; hg19: chr12-6697063;