12-6581131-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001273.5(CHD4):c.4822G>A(p.Val1608Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,614,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

CHD4
NM_001273.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:1

Conservation

PhyloP100: 2.16

Publications

7 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:

ENSG00000247853 (HGNC:58242):

ENSG00000247853 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0702959).

BP6

Variant 12-6581131-C-T is Benign according to our data. Variant chr12-6581131-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 266123.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000404 (59/1461888) while in subpopulation MID AF = 0.000693 (4/5768). AF 95% confidence interval is 0.000236. There are 0 homozygotes in GnomAdExome4. There are 36 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD4	NM_001273.5 link	c.4822G>A	p.Val1608Ile	missense_variant	Exon 33 of 40	ENST00000544040.7	NP_001264.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CHD4	ENST00000544040.7 link	c.4822G>A	p.Val1608Ile	missense_variant	Exon 33 of 40	5	NM_001273.5	ENSP00000440542.2
ENSG00000285238	ENST00000644480.2 link	n.4801G>A		non_coding_transcript_exon_variant	Exon 33 of 55			ENSP00000493629.2
ENSG00000285238	ENST00000646322.1 link	n.9+6253G>A		intron_variant	Intron 1 of 13			ENSP00000494949.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000358

AC:

AN:

251486

AF XY:

0.0000515

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1112006

Other (OTH)

AF:

0.0000828

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41538

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68010

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.544

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000667

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Sifrim-Hitz-Weiss syndrome

Pathogenic:1Uncertain:1Benign:1

Jul 23, 2019

Savagenome Genetic Health Clinic, Tarbiat Modares University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4822G>A (p.Val1608Ile) variant in CHD4 Gene has been previously reported as a pathogenic variant in clinvar (variation ID: 266123) and citation for this variant is one article with PMID: 27479907 number. controversially we found this variant in a healthy woman by Sanger sequencing, which shows it is just a benign variant. -

Dec 04, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM6,PP5,BP4. -

Mar 14, 2025

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.017

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

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.30

T;T;T;T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.043

MetaRNN

Benign

0.070

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.34

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

PhyloP100

2.2

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.50

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

REVEL

Benign

0.17

Sift

Benign

0.18

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

Sift4G

Benign

0.19

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

Polyphen

0.012, 0.0070

.;.;B;B;.;.;.;.;B;.;.;.

Vest4

0.10

MutPred

0.25

.;.;.;Gain of sheet (P = 0.0344);.;.;.;.;.;.;Gain of sheet (P = 0.0344);.;

MVP

0.29

MPC

0.035

ClinPred

0.028

GERP RS

3.6

Varity_R

0.042

gMVP

0.057

Mutation Taster

=5/95

disease causing

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over