Genetic Variant CHD4:p.Pro1654Ser (chr12-6578867-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001273.5(CHD4):c.4960C>T(p.Pro1654Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CHD4
NM_001273.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.08

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 links:

ENSG00000285238 (HGNC:):

ENSG00000285238 links:

ENSG00000247853 (HGNC:58242):

ENSG00000247853 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the CHD4 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 33 curated benign missense variants. Gene score misZ: 6.3412 (above the threshold of 3.09). Trascript score misZ: 8.6114 (above the threshold of 3.09). GenCC associations: The gene is linked to syndromic intellectual disability, Sifrim-Hitz-Weiss syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD4	NM_001273.5 link	c.4960C>T	p.Pro1654Ser	missense_variant	Exon 34 of 40	ENST00000544040.7	NP_001264.2
CHD4	NM_001297553.2 link	c.4939C>T	p.Pro1647Ser	missense_variant	Exon 33 of 39		NP_001284482.1	Q14839F5GWX5
CHD4	NM_001363606.2 link	c.4927C>T	p.Pro1643Ser	missense_variant	Exon 34 of 40		NP_001350535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHD4	ENST00000544040.7 link	c.4960C>T	p.Pro1654Ser	missense_variant	Exon 34 of 40	5	NM_001273.5	ENSP00000440542.2	Q14839-1
ENSG00000285238	ENST00000644480.2 link	n.*41C>T		non_coding_transcript_exon_variant	Exon 35 of 55			ENSP00000493629.2	A0A2R8Y445
ENSG00000285238	ENST00000644480.2 link	n.*41C>T		3_prime_UTR_variant	Exon 35 of 55			ENSP00000493629.2	A0A2R8Y445
ENSG00000285238	ENST00000646322.1 link	n.9+8517C>T		intron_variant	Intron 1 of 13			ENSP00000494949.1	A0A2R8Y5N8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

6.84e-7

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.033

.;T;.;T;.;.;.;.;.;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.58

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

0.90

.;.;.;L;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.9

.;N;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.55

Sift

Benign

0.074

.;T;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.21

.;T;.;.;.;.;.;.;.;.;.

Polyphen

1.0, 0.99

.;.;D;D;.;.;.;.;D;.;.

Vest4

0.48

MutPred

0.33

.;.;.;Gain of phosphorylation at P1654 (P = 0.0188);.;.;.;.;.;.;.;

MVP

0.72

MPC

0.041

ClinPred

0.77

GERP RS

5.7

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.1

Varity_R

0.078

gMVP

0.40

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over