ENST00000700753.1:c.205G>A

Variant names:

• chr17-7885011-G-A
• rs914983667
• ENST00000700753.1:c.205G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BS1_Supporting BS2

The ENST00000700753.1(CHD3):​c.205G>A​(p.Gly69Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,234,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000041 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: CHD3 ENST00000700753.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0340

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 Benign. Variant got -8 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). GenCC associations: The gene is linked to Snijders Blok-Campeau syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03195569).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000408 (6/146908) while in subpopulation AMR AF= 0.000338 (5/14804). AF 95% confidence interval is 0.000133. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD3	NM_001005271.3	c.205G>A	p.Gly69Ser	missense_variant	Exon 1 of 40		NP_001005271.2
CHD3	XM_005256427.5	c.205G>A	p.Gly69Ser	missense_variant	Exon 1 of 40		XP_005256484.1
CHD3	XM_006721423.4	c.205G>A	p.Gly69Ser	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.205G>A	p.Gly69Ser	missense_variant	Exon 1 of 40			ENSP00000515165.1
CHD3	ENST00000380358.9	c.205G>A	p.Gly69Ser	missense_variant	Exon 1 of 40	2		ENSP00000369716.4
NAA38	ENST00000576861.5	c.-167+154C>T		intron_variant	Intron 1 of 4	3		ENSP00000461545.1
NAA38	ENST00000570555.1	n.74+154C>T		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.0000408 AC: 6 AN: 146908 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000338

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: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000570 AC: 62 AN: 1087668 Hom.: 0 Cov.: 31 AF XY: 0.0000619 AC XY: 32 AN XY: 517266

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000313

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: 0.0000618

Gnomad4 OTH exome AF: 0.0000461

GnomAD4 genome AF: 0.0000408 AC: 6 AN: 146908 Hom.: 0 Cov.: 28 AF XY: 0.0000560 AC XY: 4 AN XY: 71458

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000338

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000152

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CHD3: PM2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	16
DANN	Benign	0.96
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.99	T
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.069
Sift	Benign	0.99	T
Sift4G	Benign	0.65	T
Vest4		0.080
MutPred		0.11		Gain of phosphorylation at G69 (P = 0.0099);
MVP		0.21
MPC		0.69
ClinPred		0.072	T
GERP RS		1.1
gMVP		0.043

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: rs914983667; hg19: chr17-7788329;