12-6573078-G-A

Variant names:

• chr12-6573078-G-A
• rs1948006247
• NM_001273.5:c.5553C>T

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.5553C>T​(p.His1851His) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000138 in 1,452,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHD4 NM_001273.5 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.75
• Publications: 0 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), G2P, Ambry Genetics
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ENSG00000285238 (HGNC:):

CHD4-AS1 (HGNC:58242):

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 (BayesDel_noAF=-0.48).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001273.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD4	NM_001273.5	MANE Select	c.5553C>T	p.His1851His	synonymous	Exon 38 of 40	NP_001264.2	Q14839-1
	CHD4	NM_001297553.2		c.5532C>T	p.His1844His	synonymous	Exon 37 of 39	NP_001284482.1	F5GWX5
	CHD4	NM_001363606.2		c.5520C>T	p.His1840His	synonymous	Exon 38 of 40	NP_001350535.1	A0A2U3TZM0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD4	ENST00000544040.7	TSL:5 MANE Select	c.5553C>T	p.His1851His	synonymous	Exon 38 of 40	ENSP00000440542.2	Q14839-1
	CHD4	ENST00000357008.7	TSL:1	c.5520C>T	p.His1840His	synonymous	Exon 38 of 40	ENSP00000349508.3	A0A2U3TZM0
	ENSG00000285238	ENST00000644480.2		n.*634C>T		non_coding_transcript_exon	Exon 39 of 55	ENSP00000493629.2	A0A2R8Y445

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452638 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722282

African (AFR) AF: 0.00 AC: 0 AN: 32830

American (AMR) AF: 0.00 AC: 0 AN: 43362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25958

East Asian (EAS) AF: 0.00 AC: 0 AN: 38928

South Asian (SAS) AF: 0.00 AC: 0 AN: 84252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5326

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108586

Other (OTH) AF: 0.00 AC: 0 AN: 60048

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.87
PhyloP100		4.8
PromoterAI		0.0071	Neutral

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: rs1948006247; hg19: chr12-6682244;