ENST00000700753.1:c.190C>T

Variant names:

• chr17-7884996-C-T
• ENST00000700753.1:c.190C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000700753.1(CHD3):​c.190C>T​(p.Arg64Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,092,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CHD3 ENST00000700753.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.229

Genes affected

CHD3 (HGNC:1918): (chromodomain helicase DNA binding protein 3) This gene encodes a member of the CHD family of proteins which are characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. This protein is one of the components of a histone deacetylase complex referred to as the Mi-2/NuRD complex which participates in the remodeling of chromatin by deacetylating histones. Chromatin remodeling is essential for many processes including transcription. Autoantibodies against this protein are found in a subset of patients with dermatomyositis. Three alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

NAA38 (HGNC:28212): (N-alpha-acetyltransferase 38, NatC auxiliary subunit) Involved in negative regulation of apoptotic process. Located in cytoplasm and nucleoplasm. Part of NatC complex. Colocalizes with polysome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CHD3 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 39 curated benign missense variants. Gene score misZ: 6.1518 (above the threshold of 3.09). GenCC associations: The gene is linked to Snijders Blok-Campeau syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18120056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD3	NM_001005271.3	c.190C>T	p.Arg64Cys	missense_variant	Exon 1 of 40		NP_001005271.2
CHD3	XM_005256427.5	c.190C>T	p.Arg64Cys	missense_variant	Exon 1 of 40		XP_005256484.1
CHD3	XM_006721423.4	c.190C>T	p.Arg64Cys	missense_variant	Exon 1 of 40		XP_006721486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD3	ENST00000700753.1	c.190C>T	p.Arg64Cys	missense_variant	Exon 1 of 40			ENSP00000515165.1
CHD3	ENST00000380358.9	c.190C>T	p.Arg64Cys	missense_variant	Exon 1 of 40	2		ENSP00000369716.4
NAA38	ENST00000576861.5	c.-167+169G>A		intron_variant	Intron 1 of 4	3		ENSP00000461545.1
NAA38	ENST00000570555.1	n.74+169G>A		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000275 AC: 3 AN: 1092642 Hom.: 0 Cov.: 30 AF XY: 0.00000192 AC XY: 1 AN XY: 519666

Gnomad4 AFR exome AF: 0.00

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: 0.00000325

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 05, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter 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
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Benign	0.96
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.36	T
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.17	T
Vest4		0.072
MutPred		0.18		Loss of methylation at R60 (P = 0.1301);
MVP		0.42
MPC		0.94
ClinPred		0.67	D
gMVP		0.16

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: chr17-7788314;