dbSNP rs1046714373: CHD4:p.Ala1876Ser (chr12-6570964-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001273.5(CHD4):c.5626G>T(p.Ala1876Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1876T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CHD4
NM_001273.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.97

Publications

0 publications found

Variant links:

Genes affected

CHD4 (HGNC:1919): (chromodomain helicase DNA binding protein 4) The product of this gene belongs to the SNF2/RAD54 helicase family. It represents the main component of the nucleosome remodeling and deacetylase complex and plays an important role in epigenetic transcriptional repression. Patients with dermatomyositis develop antibodies against this protein. Somatic mutations in this gene are associated with serous endometrial tumors. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2014]

CHD4 Gene-Disease associations (from GenCC):

Sifrim-Hitz-Weiss syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

CHD4 links:

ENSG00000285238 (HGNC:):

ENSG00000285238 links:

CHD4-AS1 (HGNC:58242):

CHD4-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31009018).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001273.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHD4	NM_001273.5	MANE Select	c.5626G>T	p.Ala1876Ser	missense	Exon 39 of 40	NP_001264.2	Q14839-1
CHD4	NM_001297553.2		c.5605G>T	p.Ala1869Ser	missense	Exon 38 of 39	NP_001284482.1	F5GWX5
CHD4	NM_001363606.2		c.5596G>T	p.Ala1866Ser	missense	Exon 39 of 40	NP_001350535.1	A0A2U3TZM0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHD4	ENST00000544040.7	TSL:5 MANE Select	c.5626G>T	p.Ala1876Ser	missense	Exon 39 of 40	ENSP00000440542.2	Q14839-1
CHD4	ENST00000357008.7	TSL:1	c.5596G>T	p.Ala1866Ser	missense	Exon 39 of 40	ENSP00000349508.3	A0A2U3TZM0
ENSG00000285238	ENST00000644480.2		n.*707G>T		non_coding_transcript_exon	Exon 40 of 55	ENSP00000493629.2	A0A2R8Y445

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.071

MetaRNN

Benign

0.31

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

-0.32

PhyloP100

3.0

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.44

Sift

Benign

0.42

Sift4G

Benign

0.85

Polyphen

0.094

Vest4

0.32

MutPred

0.41

Gain of disorder (P = 0.0556)

MVP

0.69

MPC

1.9

ClinPred

0.55

GERP RS

5.7

Varity_R

0.20

gMVP

0.62

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over