ENST00000700753.1:c.70G>T

Variant names:

• chr17-7884876-G-T
• rs1967499226
• NM_001437504.1:c.70G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000700753.1(CHD3):​c.70G>T​(p.Glu24*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000856 in 1,168,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: CHD3 ENST00000700753.1 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 122 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000700753.1. 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.70G>T	p.Glu24*	stop_gained	Exon 1 of 40	NP_001424433.1	A0A8V8TR54
	CHD3	NM_001005271.3		c.70G>T	p.Glu24*	stop_gained	Exon 1 of 40	NP_001005271.2	Q12873-3
	CHD3	NM_001437509.1		c.70G>T	p.Glu24*	stop_gained	Exon 1 of 40	NP_001424438.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD3	ENST00000700753.1		c.70G>T	p.Glu24*	stop_gained	Exon 1 of 40	ENSP00000515165.1	A0A8V8TR54
	CHD3	ENST00000380358.9	TSL:2	c.70G>T	p.Glu24*	stop_gained	Exon 1 of 40	ENSP00000369716.4	Q12873-3
	NAA38	ENST00000576861.5	TSL:3	c.-167+289C>A		intron	N/A	ENSP00000461545.1	I3L4V0

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 8.56e-7 AC: 1 AN: 1168850 Hom.: 0 Cov.: 16 AF XY: 0.00000172 AC XY: 1 AN XY: 581296

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24720

American (AMR) AF: 0.0000351 AC: 1 AN: 28462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20942

East Asian (EAS) AF: 0.00 AC: 0 AN: 27712

South Asian (SAS) AF: 0.00 AC: 0 AN: 65356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3484

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 914596

Other (OTH) AF: 0.00 AC: 0 AN: 48094

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Uncertain	0.19
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.36	N
PhyloP100		1.1
Vest4		0.34
GERP RS		0.14
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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: rs1967499226; hg19: chr17-7788194;