12-6601981-C-G

Variant names:

• chr12-6601981-C-G
• rs1639122
• NM_001273.5:c.417G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001273.5(CHD4):​c.417G>C​(p.Glu139Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000667 in 149,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: 𝑓 0.0000067 (0 hom., cov: 27)
• Consequence: CHD4 NM_001273.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.27
• Publications: 56 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026313335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD4	NM_001273.5	c.417G>C	p.Glu139Asp	missense_variant	Exon 4 of 40	ENST00000544040.7	NP_001264.2
CHD4	NM_001297553.2	c.396G>C	p.Glu132Asp	missense_variant	Exon 3 of 39		NP_001284482.1
CHD4	NM_001363606.2	c.417G>C	p.Glu139Asp	missense_variant	Exon 4 of 40		NP_001350535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD4	ENST00000544040.7	c.417G>C	p.Glu139Asp	missense_variant	Exon 4 of 40	5	NM_001273.5	ENSP00000440542.2
ENSG00000285238	ENST00000644480.2	n.396G>C		non_coding_transcript_exon_variant	Exon 4 of 55			ENSP00000493629.2

Frequencies

GnomAD3 genomes AF: 0.00000667 AC: 1 AN: 149990 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 40

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 149990 Hom.: 0 Cov.: 27 AF XY: 0.0000137 AC XY: 1 AN XY: 73106

African (AFR) AF: 0.00 AC: 0 AN: 40428

American (AMR) AF: 0.00 AC: 0 AN: 15100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5086

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67622

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.00 Hom.: 54444

Bravo AF: 0.00000756

ExAC AF: 0.0000167 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.0010
DANN	Benign	0.073
DEOGEN2	Benign	0.0074	.;T;.;T;.;.;.;.;.;.;.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.026	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	-0.37	.;.;.;N;.;.;.;.;N;.;.;.
PhyloP100		-2.3
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.95	N;N;.;.;.;.;.;.;.;.;.;N
REVEL	Benign	0.22
Sift	Benign	1.0	T;T;.;.;.;.;.;.;.;.;.;T
Sift4G	Benign	0.72	T;T;.;.;.;.;.;.;.;.;.;T
Polyphen		0.0	.;.;B;B;.;.;.;.;B;.;.;.
Vest4		0.10
MutPred		0.12		Loss of stability (P = 0.1508);.;.;Loss of stability (P = 0.1508);.;.;.;Loss of stability (P = 0.1508);Loss of stability (P = 0.1508);Loss of stability (P = 0.1508);.;Loss of stability (P = 0.1508);
MVP		0.28
MPC		0.0082
ClinPred		0.025	T
GERP RS		-8.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7
Varity_R		0.020
gMVP		0.33
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs1639122; hg19: chr12-6711147;