chr12-6573159-C-G

Position:

• chr12-6573159-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001273.5(CHD4):​c.5472G>C​(p.Glu1824Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD4 NM_001273.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CHD4. . Gene score misZ 6.3412 (greater than the threshold 3.09). Trascript score misZ 8.6114 (greater than threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, Sifrim-Hitz-Weiss syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD4	NM_001273.5	c.5472G>C	p.Glu1824Asp	missense_variant	38/40	ENST00000544040.7
CHD4	NM_001297553.2	c.5451G>C	p.Glu1817Asp	missense_variant	37/39
CHD4	NM_001363606.2	c.5439G>C	p.Glu1813Asp	missense_variant	38/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD4	ENST00000544040.7	c.5472G>C	p.Glu1824Asp	missense_variant	38/40	5	NM_001273.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sifrim-Hitz-Weiss syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Sep 05, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	.;T;.;T;.;.;.;.;.;.;.
Eigen	Benign	-0.034
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.1	.;.;.;L;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.6	.;D;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.75
Sift	Benign	0.13	.;T;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.11	.;T;.;.;.;.;.;.;.;.;.
Polyphen		0.32, 1.0, 0.99	.;.;B;D;.;.;.;.;D;.;.
Vest4		0.73
MutPred		0.67		.;.;.;Loss of disorder (P = 0.0943);.;.;.;.;.;.;.;
MVP		0.91
MPC		1.9
ClinPred		0.96	D
GERP RS		3.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.41
gMVP		0.61

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: rs1271091451; hg19: chr12-6682325;