rs1639122

chr12-6601981-C-Achr12-6601981-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001273.5(CHD4):c.417G>T(p.Glu139Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 1,554,978 control chromosomes in the GnomAD database, including 133,688 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.53 (23964 hom., cov: 27)
  • Exomes 𝑓: 0.42 (109724 hom.)
• Consequence: CHD4 NM_001273.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.27

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CHD4
• BP4: Computational evidence support a benign effect (MetaRNN=2.4436306E-6).
• BP6: Variant 12-6601981-C-A is Benign according to our data. Variant chr12-6601981-C-A is described in ClinVar as [Benign]. Clinvar id is 1209824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD4	NM_001273.5	c.417G>T	p.Glu139Asp	missense_variant	4/40	ENST00000544040.7
CHD4	NM_001297553.2	c.396G>T	p.Glu132Asp	missense_variant	3/39
CHD4	NM_001363606.2	c.417G>T	p.Glu139Asp	missense_variant	4/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD4	ENST00000544040.7	c.417G>T	p.Glu139Asp	missense_variant	4/40	5	NM_001273.5	A1

Frequencies

GnomAD3 genomes AF: 0.532 AC: 79635 AN: 149584 Hom.: 23935 Cov.: 27

Gnomad AFR AF: 0.841

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.496

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.438

GnomAD3 exomes AF: 0.399 AC: 90088 AN: 226028 Hom.: 14508 AF XY: 0.391 AC XY: 48464 AN XY: 123984

Gnomad AFR exome AF: 0.750

Gnomad AMR exome AF: 0.354

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.401

Gnomad SAS exome AF: 0.381

Gnomad FIN exome AF: 0.462

Gnomad NFE exome AF: 0.379

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.421 AC: 591468 AN: 1405284 Hom.: 109724 Cov.: 40 AF XY: 0.418 AC XY: 292562 AN XY: 700040

Gnomad4 AFR exome AF: 0.781

Gnomad4 AMR exome AF: 0.373

Gnomad4 ASJ exome AF: 0.264

Gnomad4 EAS exome AF: 0.414

Gnomad4 SAS exome AF: 0.402

Gnomad4 FIN exome AF: 0.482

Gnomad4 NFE exome AF: 0.416

Gnomad4 OTH exome AF: 0.423

GnomAD4 genome AF: 0.533 AC: 79725 AN: 149694 Hom.: 23964 Cov.: 27 AF XY: 0.529 AC XY: 38651 AN XY: 73000

Gnomad4 AFR AF: 0.840

Gnomad4 AMR AF: 0.407

Gnomad4 ASJ AF: 0.269

Gnomad4 EAS AF: 0.444

Gnomad4 SAS AF: 0.410

Gnomad4 FIN AF: 0.496

Gnomad4 NFE AF: 0.417

Gnomad4 OTH AF: 0.440

Alfa AF: 0.402 Hom.: 20784

Bravo AF: 0.541

TwinsUK AF: 0.442 AC: 1640

ALSPAC AF: 0.444 AC: 1711

ESP6500AA AF: 0.826 AC: 3616

ESP6500EA AF: 0.407 AC: 3488

ExAC AF: 0.421 AC: 50316

Asia WGS AF: 0.495 AC: 1719 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sifrim-Hitz-Weiss syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	0.0010
Dann	Benign	0.12
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0000024	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	P;P;P;P
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);
MPC		0.0082
ClinPred		0.0026	T
GERP RS		-8.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7
Varity_R		0.020
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs1639122; hg19: chr12-6711147; COSMIC: COSV58895130; COSMIC: COSV58895130;