chr17-7884894-G-A

Variant names:

• chr17-7884894-G-A
• rs770625965
• ENST00000700753.1:c.88G>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001005271.3(CHD3):​c.88G>A​(p.Glu30Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,085,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CHD3 NM_001005271.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

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 Likely_benign. Variant got -5 ACMG points.

• 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). Trascript score misZ: 8.0663 (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=0.19891885).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD3	NM_001005271.3	c.88G>A	p.Glu30Lys	missense_variant	Exon 1 of 40		NP_001005271.2
CHD3	XM_005256427.5	c.88G>A	p.Glu30Lys	missense_variant	Exon 1 of 40		XP_005256484.1
CHD3	XM_006721423.4	c.88G>A	p.Glu30Lys	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.88G>A	p.Glu30Lys	missense_variant	Exon 1 of 40			ENSP00000515165.1
CHD3	ENST00000380358.9	c.88G>A	p.Glu30Lys	missense_variant	Exon 1 of 40	2		ENSP00000369716.4
NAA38	ENST00000576861.5	c.-167+271C>T		intron_variant	Intron 1 of 4	3		ENSP00000461545.1
NAA38	ENST00000570555.1	n.74+271C>T		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149342 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000300

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000961 AC: 9 AN: 936322 Hom.: 0 Cov.: 18 AF XY: 0.00000866 AC XY: 4 AN XY: 461904

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: 0.0000122

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000134 AC: 2 AN: 149342 Hom.: 0 Cov.: 27 AF XY: 0.0000137 AC XY: 1 AN XY: 72744

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000300

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000108 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 02, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this 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	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Uncertain	0.97
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.42	T
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.24	N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.82	T
Vest4		0.15
MutPred		0.12		Gain of glycosylation at E30 (P = 0.0106);
MVP		0.52
MPC		0.78
ClinPred		0.58	D
GERP RS		0.38
gMVP		0.048

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: rs770625965; hg19: chr17-7788212;