rs1639122

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-6601981-C-A
• chr12-6601981-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:3 O:1
• 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: Benign. The variant received -20 ACMG points.

• 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 VariationId 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 rank	MANE	Protein	UniProt
CHD4	NM_001273.5	c.417G>T	p.Glu139Asp	missense_variant	Exon 4 of 40	ENST00000544040.7	NP_001264.2
CHD4	NM_001297553.2	c.396G>T	p.Glu132Asp	missense_variant	Exon 3 of 39		NP_001284482.1
CHD4	NM_001363606.2	c.417G>T	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>T	p.Glu139Asp	missense_variant	Exon 4 of 40	5	NM_001273.5	ENSP00000440542.2
ENSG00000285238	ENST00000644480.2	n.396G>T		non_coding_transcript_exon_variant	Exon 4 of 55			ENSP00000493629.2

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

GnomAD2 exomes AF: 0.399 AC: 90088 AN: 226028 AF XY: 0.391

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 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

African (AFR) AF: 0.781 AC: 25291 AN: 32390

American (AMR) AF: 0.373 AC: 16215 AN: 43476

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 6621 AN: 25116

East Asian (EAS) AF: 0.414 AC: 16076 AN: 38792

South Asian (SAS) AF: 0.402 AC: 33637 AN: 83676

European-Finnish (FIN) AF: 0.482 AC: 21163 AN: 43880

Middle Eastern (MID) AF: 0.276 AC: 1542 AN: 5594

European-Non Finnish (NFE) AF: 0.416 AC: 446253 AN: 1073998

Other (OTH) AF: 0.423 AC: 24670 AN: 58362

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

African (AFR) AF: 0.840 AC: 34023 AN: 40482

American (AMR) AF: 0.407 AC: 6130 AN: 15054

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 930 AN: 3462

East Asian (EAS) AF: 0.444 AC: 2244 AN: 5054

South Asian (SAS) AF: 0.410 AC: 1941 AN: 4730

European-Finnish (FIN) AF: 0.496 AC: 5048 AN: 10174

Middle Eastern (MID) AF: 0.271 AC: 79 AN: 292

European-Non Finnish (NFE) AF: 0.417 AC: 28097 AN: 67456

Other (OTH) AF: 0.440 AC: 918 AN: 2084

Alfa AF: 0.435 Hom.: 54444

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:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sifrim-Hitz-Weiss syndrome Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thalidomide response Other:1

-

Rare Diseases Genetics and Genomics, Islamia College Peshawar

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

this variant was associated with excellent response to thalidomide (achieving transfusion independence) excellent responsive

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
DEOGEN2	Benign	0.0074	.;T;.;T;.;.;.;.;.;.;.;T
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
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);
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
Mutation Taster		=84/16	polymorphism

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