12-6587756-T-G

Position:

• chr12-6587756-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The NM_001273.5(CHD4):​c.3659A>C​(p.Lys1220Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD4 NM_001273.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.98

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 gene, where missense usually causes diseases (based on misZ statistic), CHD4. . Gene score misZ 6.3412 (greater than the threshold 3.09). Trascript score misZ 8.6114 (greater than threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, Sifrim-Hitz-Weiss syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77
• PP5: Variant 12-6587756-T-G is Pathogenic according to our data. Variant chr12-6587756-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 520917.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD4	NM_001273.5	c.3659A>C	p.Lys1220Thr	missense_variant	24/40	ENST00000544040.7	NP_001264.2
CHD4	NM_001297553.2	c.3638A>C	p.Lys1213Thr	missense_variant	23/39		NP_001284482.1
CHD4	NM_001363606.2	c.3620A>C	p.Lys1207Thr	missense_variant	24/40		NP_001350535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD4	ENST00000544040.7	c.3659A>C	p.Lys1220Thr	missense_variant	24/40	5	NM_001273.5	ENSP00000440542.2
ENSG00000285238	ENST00000644480.2	n.3638A>C		non_coding_transcript_exon_variant	24/55			ENSP00000493629.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 10, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.3659A>C (p.K1220T) alteration is located in exon 24 (coding exon 23) of the CHD4 gene. This alteration results from a A to C substitution at nucleotide position 3659, causing the lysine (K) at amino acid position 1220 to be replaced by a threonine (T). The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the CHD4 c.3659A>C alteration was not observed, with coverage at this position. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.K1220 amino acid is conserved in available vertebrate species. The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ The in silico prediction for the p.K1220T alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 27, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;T;.;T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.7	.;.;.;M;.;.;.;.;M;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.8	.;D;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	.;D;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.010	.;D;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0, 0.0010, 0.0070	.;.;D;B;.;.;.;.;B;.;.;.
Vest4		0.80
MutPred		0.49		.;.;.;Loss of ubiquitination at K1220 (P = 0.0071);.;.;.;.;Loss of ubiquitination at K1220 (P = 0.0071);.;Loss of ubiquitination at K1220 (P = 0.0071);.;
MVP		0.92
MPC		1.9
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.75
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs1377989582; hg19: chr12-6696922;