Genetic Variant NM_001273.5:c.5362-852C>T (chr12-6574121-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001273.5(CHD4):c.5362-852C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 151,986 control chromosomes in the GnomAD database, including 9,645 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 9645 hom., cov: 32)

Consequence

CHD4
NM_001273.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.335

Publications

14 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), Ambry Genetics, G2P
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

CHD4 links:

ENSG00000285238 (HGNC:):

ENSG00000285238 links:

CHD4-AS1 (HGNC:58242):

CHD4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD4	NM_001273.5 link	c.5362-852C>T		intron_variant	Intron 37 of 39	ENST00000544040.7	NP_001264.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CHD4	ENST00000544040.7 link	c.5362-852C>T	intron_variant	Intron 37 of 39	5	NM_001273.5	ENSP00000440542.2
ENSG00000285238	ENST00000644480.2 link	n.*443-852C>T	intron_variant	Intron 38 of 54			ENSP00000493629.2
ENSG00000285238	ENST00000646322.1 link	n.10-7504C>T	intron_variant	Intron 1 of 13			ENSP00000494949.1

Frequencies

GnomAD3 genomes

AF:

0.302

AC:

45794

AN:

151868

Hom.:

9620

Cov.:

show subpopulations

Gnomad AFR

AF:

0.604

Gnomad AMI

AF:

0.112

Gnomad AMR

AF:

0.186

Gnomad ASJ

AF:

0.170

Gnomad EAS

AF:

0.277

Gnomad SAS

AF:

0.226

Gnomad FIN

AF:

0.248

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.171

Gnomad OTH

AF:

0.238

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.302

AC:

45868

AN:

151986

Hom.:

9645

Cov.:

AF XY:

0.302

AC XY:

22421

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.604

AC:

25029

AN:

41428

American (AMR)

AF:

0.185

AC:

2829

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.170

AC:

590

AN:

3470

East Asian (EAS)

AF:

0.276

AC:

1426

AN:

5168

South Asian (SAS)

AF:

0.226

AC:

1091

AN:

4822

European-Finnish (FIN)

AF:

0.248

AC:

2616

AN:

10536

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.171

AC:

11620

AN:

67982

Other (OTH)

AF:

0.238

AC:

503

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1374

2748

4121

5495

6869

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

422

844

1266

1688

2110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.210

Hom.:

14109

Bravo

AF:

0.309

Asia WGS

AF:

0.291

AC:

1012

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

7.0

(source)

DANN

Benign

0.73

PhyloP100

0.34

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over