chr12-6573091-T-C

Variant names:

• chr12-6573091-T-C
• NM_001273.5:c.5540A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001273.5(CHD4):​c.5540A>G​(p.Asn1847Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CHD4 NM_001273.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.99
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

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.5540A>G	p.Asn1847Ser	missense	Exon 38 of 40	NP_001264.2	Q14839-1
	CHD4	NM_001297553.2		c.5519A>G	p.Asn1840Ser	missense	Exon 37 of 39	NP_001284482.1	F5GWX5
	CHD4	NM_001363606.2		c.5507A>G	p.Asn1836Ser	missense	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.5540A>G	p.Asn1847Ser	missense	Exon 38 of 40	ENSP00000440542.2	Q14839-1
	CHD4	ENST00000357008.7	TSL:1	c.5507A>G	p.Asn1836Ser	missense	Exon 38 of 40	ENSP00000349508.3	A0A2U3TZM0
	ENSG00000285238	ENST00000644480.2		n.*621A>G		non_coding_transcript_exon	Exon 39 of 55	ENSP00000493629.2	A0A2R8Y445

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457454 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724836

African (AFR) AF: 0.0000301 AC: 1 AN: 33186

American (AMR) AF: 0.00 AC: 0 AN: 44188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39334

South Asian (SAS) AF: 0.00 AC: 0 AN: 85212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5532

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110322

Other (OTH) AF: 0.00 AC: 0 AN: 60222

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.76
Sift	Benign	0.035	D
Sift4G	Uncertain	0.030	D
Polyphen		0.50	P
Vest4		0.71
MutPred		0.80		Gain of disorder (P = 0.0727)
MVP		0.91
MPC		1.8
ClinPred		0.99	D
GERP RS		5.7
PromoterAI		-0.037	Neutral
Varity_R		0.46
gMVP		0.62
Mutation Taster		=42/58	disease causing

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

hg19: chr12-6682257;