12-6570874-G-A

Variant names:

• chr12-6570874-G-A
• NM_001273.5:c.5716C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001273.5(CHD4):​c.5716C>T​(p.Gln1906*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: CHD4 NM_001273.5 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.75

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 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00401 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD4	NM_001273.5	c.5716C>T	p.Gln1906*	stop_gained	Exon 39 of 40	ENST00000544040.7	NP_001264.2
CHD4	NM_001297553.2	c.5695C>T	p.Gln1899*	stop_gained	Exon 38 of 39		NP_001284482.1
CHD4	NM_001363606.2	c.5686C>T	p.Gln1896*	stop_gained	Exon 39 of 40		NP_001350535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD4	ENST00000544040.7	c.5716C>T	p.Gln1906*	stop_gained	Exon 39 of 40	5	NM_001273.5	ENSP00000440542.2
ENSG00000285238	ENST00000644480.2	n.*797C>T		non_coding_transcript_exon_variant	Exon 40 of 55			ENSP00000493629.2
ENSG00000285238	ENST00000644480.2	n.*797C>T		3_prime_UTR_variant	Exon 40 of 55			ENSP00000493629.2
ENSG00000285238	ENST00000646322.1	n.10-4257C>T		intron_variant	Intron 1 of 13			ENSP00000494949.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 02, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last 7 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.70
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: chr12-6680040; COSMIC: COSV58901643; COSMIC: COSV58901643;