rs3763592

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017780.4(CHD7):c.6103+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0572 in 1,613,390 control chromosomes in the GnomAD database, including 7,029 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 3121 hom., cov: 32)

Exomes 𝑓: 0.049 ( 3908 hom. )

Consequence

CHD7
NM_017780.4 splice_region, intron

Scores

Splicing: ADA: 0.00002795

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.0930

Publications

10 publications found

Variant links:

Genes affected

CHD7 (HGNC:20626): (chromodomain helicase DNA binding protein 7) This gene encodes a protein that contains several helicase family domains. Mutations in this gene have been found in some patients with the CHARGE syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

CHD7 Gene-Disease associations (from GenCC):

CHARGE syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Broad Center for Mendelian Genomics, ClinGen, G2P
hypogonadotropic hypogonadism 5 with or without anosmia
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hypogonadotropic hypogonadism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Kallmann syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Omenn syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CHD7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 8-60852714-C-T is Benign according to our data. Variant chr8-60852714-C-T is described in ClinVar as Benign. ClinVar VariationId is 95799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD7	NM_017780.4 link	c.6103+8C>T		splice_region_variant, intron_variant	Intron 30 of 37	ENST00000423902.7	NP_060250.2	Q9P2D1-1Q6ZWF9

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHD7	ENST00000423902.7 link	c.6103+8C>T	splice_region_variant, intron_variant	Intron 30 of 37	5	NM_017780.4	ENSP00000392028.1	Q9P2D1-1
CHD7	ENST00000524602.5 link	c.1717-9515C>T	intron_variant	Intron 2 of 4	1		ENSP00000437061.1	Q9P2D1-4
CHD7	ENST00000695853.1 link	n.6103+8C>T	splice_region_variant, intron_variant	Intron 30 of 36			ENSP00000512218.1	A0A8Q3WKT9
CHD7	ENST00000527921.1 link	n.*75C>T	downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.138

AC:

20950

AN:

151966

Hom.:

3120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.374

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0711

Gnomad ASJ

AF:

0.0688

Gnomad EAS

AF:

0.0164

Gnomad SAS

AF:

0.0478

Gnomad FIN

AF:

0.0757

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0411

Gnomad OTH

AF:

0.120

GnomAD2 exomes

AF:

0.0662

AC:

16489

AN:

249032

AF XY:

0.0611

show subpopulations

Gnomad AFR exome

AF:

0.386

Gnomad AMR exome

AF:

0.0398

Gnomad ASJ exome

AF:

0.0749

Gnomad EAS exome

AF:

0.0132

Gnomad FIN exome

AF:

0.0806

Gnomad NFE exome

AF:

0.0411

Gnomad OTH exome

AF:

0.0589

GnomAD4 exome

AF:

0.0488

AC:

71363

AN:

1461306

Hom.:

3908

Cov.:

AF XY:

0.0476

AC XY:

34633

AN XY:

726954

show subpopulations

African (AFR)

AF:

0.385

AC:

12883

AN:

33452

American (AMR)

AF:

0.0446

AC:

1996

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0755

AC:

1972

AN:

26132

East Asian (EAS)

AF:

0.0166

AC:

657

AN:

39694

South Asian (SAS)

AF:

0.0475

AC:

4099

AN:

86250

European-Finnish (FIN)

AF:

0.0783

AC:

4180

AN:

53370

Middle Eastern (MID)

AF:

0.0740

AC:

427

AN:

5768

European-Non Finnish (NFE)

AF:

0.0371

AC:

41265

AN:

1111558

Other (OTH)

AF:

0.0643

AC:

3884

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

3500

7000

10501

14001

17501

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1716

3432

5148

6864

8580

<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:

0.138

AC:

20973

AN:

152084

Hom.:

3121

Cov.:

AF XY:

0.137

AC XY:

10165

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.373

AC:

15458

AN:

41430

American (AMR)

AF:

0.0710

AC:

1086

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0688

AC:

239

AN:

3472

East Asian (EAS)

AF:

0.0162

AC:

AN:

5176

South Asian (SAS)

AF:

0.0473

AC:

228

AN:

4824

European-Finnish (FIN)

AF:

0.0757

AC:

801

AN:

10580

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0410

AC:

2790

AN:

67986

Other (OTH)

AF:

0.119

AC:

251

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

742

1483

2225

2966

3708

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

190

380

570

760

950

<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:

0.0705

Hom.:

4083

Bravo

AF:

0.145

Asia WGS

AF:

0.0490

AC:

172

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 03, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 21, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.6103+8C>T in intron 30 of CHD7: This variant is not expected to have clinical significance because it has been identified in 38.25% (9168/23972) of African ch romosomes including 1772 homozygotes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs3763592). ACMG/AMP criteria applied: BA1. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 24, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Jul 25, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22033296, 27884173, 16400610, 21158681) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

CHARGE syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypogonadotropic hypogonadism 5 with or without anosmia

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

5.1

(source)

DANN

Benign

0.55

PhyloP100

-0.093

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000028

dbscSNV1_RF

Benign

0.0

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