rs914983667

Variant names:

• chr17-7885011-G-A
• rs914983667
• NM_001437504.1:c.205G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001437504.1(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. 13/20 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 NM_001437504.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0340
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• 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 the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001437504.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD3	NM_001437504.1		c.205G>A	p.Gly69Ser	missense	Exon 1 of 40	NP_001424433.1	A0A8V8TR54
	CHD3	NM_001005271.3		c.205G>A	p.Gly69Ser	missense	Exon 1 of 40	NP_001005271.2	Q12873-3
	CHD3	NM_001437509.1		c.205G>A	p.Gly69Ser	missense	Exon 1 of 40	NP_001424438.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD3	ENST00000700753.1		c.205G>A	p.Gly69Ser	missense	Exon 1 of 40	ENSP00000515165.1	A0A8V8TR54
	CHD3	ENST00000380358.9	TSL:2	c.205G>A	p.Gly69Ser	missense	Exon 1 of 40	ENSP00000369716.4	Q12873-3
	NAA38	ENST00000576861.5	TSL:3	c.-167+154C>T		intron	N/A	ENSP00000461545.1	I3L4V0

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

African (AFR) AF: 0.00 AC: 0 AN: 22652

American (AMR) AF: 0.000313 AC: 3 AN: 9600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14350

East Asian (EAS) AF: 0.00 AC: 0 AN: 26222

South Asian (SAS) AF: 0.00 AC: 0 AN: 21582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2942

European-Non Finnish (NFE) AF: 0.0000618 AC: 57 AN: 922620

Other (OTH) AF: 0.0000461 AC: 2 AN: 43422

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

African (AFR) AF: 0.00 AC: 0 AN: 40778

American (AMR) AF: 0.000338 AC: 5 AN: 14804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 5066

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65982

Other (OTH) AF: 0.00 AC: 0 AN: 2020

Alfa AF: 0.0000712 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
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
PhyloP100		0.034
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
PromoterAI		-0.036	Neutral
gMVP		0.043
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs914983667; hg19: chr17-7788329;