12-6573091-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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]

ENSG00000285238 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CHD4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 33 curated benign missense variants. Gene score misZ: 6.3412 (above the threshold of 3.09). Trascript score misZ: 8.6114 (above the threshold of 3.09). GenCC associations: The gene is linked to syndromic intellectual disability, Sifrim-Hitz-Weiss syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD4	NM_001273.5	c.5540A>G	p.Asn1847Ser	missense_variant	Exon 38 of 40	ENST00000544040.7	NP_001264.2
CHD4	NM_001297553.2	c.5519A>G	p.Asn1840Ser	missense_variant	Exon 37 of 39		NP_001284482.1
CHD4	NM_001363606.2	c.5507A>G	p.Asn1836Ser	missense_variant	Exon 38 of 40		NP_001350535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD4	ENST00000544040.7	c.5540A>G	p.Asn1847Ser	missense_variant	Exon 38 of 40	5	NM_001273.5	ENSP00000440542.2
ENSG00000285238	ENST00000644480.2	n.*621A>G		non_coding_transcript_exon_variant	Exon 39 of 55			ENSP00000493629.2
ENSG00000285238	ENST00000644480.2	n.*621A>G		3_prime_UTR_variant	Exon 39 of 55			ENSP00000493629.2
ENSG00000285238	ENST00000646322.1	n.10-6474A>G		intron_variant	Intron 1 of 13			ENSP00000494949.1

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

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5540A>G (p.N1847S) alteration is located in exon 38 (coding exon 37) of the CHD4 gene. This alteration results from a A to G substitution at nucleotide position 5540, causing the asparagine (N) at amino acid position 1847 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;.;T;.;.;.;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.6	.;.;.;M;.;.;.;.;.;.;.
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, 1.0, 0.99	.;.;P;D;.;.;.;.;D;.;.
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
Varity_R		0.46
gMVP		0.62

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-6682257;