17-7885005-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2

The NM_001005271.3(CHD3):c.199C>T(p.Pro67Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,240,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000055 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000073 ( 0 hom. )

Consequence

CHD3
NM_001005271.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.05

Variant links:

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]

CHD3 links:

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]

NAA38 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 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=0.122982174).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000546 (8/146614) while in subpopulation AFR AF= 0.000197 (8/40624). AF 95% confidence interval is 0.0000973. 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 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
CHD3	NM_001005271.3 link	c.199C>T	p.Pro67Ser	missense_variant	Exon 1 of 40	NP_001005271.2	Q12873-3Q2TAZ1B3KWV4
CHD3	XM_005256427.5 link	c.199C>T	p.Pro67Ser	missense_variant	Exon 1 of 40	XP_005256484.1
CHD3	XM_006721423.4 link	c.199C>T	p.Pro67Ser	missense_variant	Exon 1 of 40	XP_006721486.1	A0A8V8TR54

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
CHD3	ENST00000700753.1 link	c.199C>T	p.Pro67Ser	missense_variant	Exon 1 of 40		ENSP00000515165.1	A0A8V8TR54
CHD3	ENST00000380358.9 link	c.199C>T	p.Pro67Ser	missense_variant	Exon 1 of 40	2	ENSP00000369716.4	Q12873-3
NAA38	ENST00000576861.5 link	c.-167+160G>A		intron_variant	Intron 1 of 4	3	ENSP00000461545.1	I3L4V0
NAA38	ENST00000570555.1 link	n.74+160G>A		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.0000546

AC:

AN:

146614

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000197

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000731

AC:

AN:

1094096

Hom.:

Cov.:

AF XY:

0.00000768

AC XY:

AN XY:

521112

show subpopulations

Gnomad4 AFR exome

AF:

0.0000879

Gnomad4 AMR exome

AF:

0.000101

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:

0.00000324

Gnomad4 OTH exome

AF:

0.0000458

GnomAD4 genome

AF:

0.0000546

AC:

AN:

146614

Hom.:

Cov.:

AF XY:

0.0000561

AC XY:

AN XY:

71324

show subpopulations

Gnomad4 AFR

AF:

0.000197

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.199C>T (p.P67S) alteration is located in exon 1 (coding exon 1) of the CHD3 gene. This alteration results from a C to T substitution at nucleotide position 199, causing the proline (P) at amino acid position 67 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.96

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.67

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.060

REVEL

Benign

0.19

Sift

Benign

0.43

Sift4G

Benign

0.45

Vest4

0.15

MutPred

0.16

Gain of phosphorylation at P67 (P = 0.0073);

MVP

0.32

MPC

0.70

ClinPred

0.075

GERP RS

-0.17

gMVP

0.092

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over