Genetic Variant CHD7:c.-472_-467dupGGCGGC (chr8-60678764-C-CGCGGCG) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_017780.4(CHD7):c.-472_-467dupGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.092 ( 801 hom., cov: 0)

Exomes 𝑓: 0.069 ( 3 hom. )

Consequence

CHD7
NM_017780.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.400

Publications

2 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Broad Center for Mendelian Genomics, ClinGen
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 -8 ACMG points.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017780.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD7	NM_017780.4	MANE Select	c.-472_-467dupGGCGGC		5_prime_UTR	Exon 1 of 38	NP_060250.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHD7	ENST00000423902.7	TSL:5 MANE Select	c.-472_-467dupGGCGGC	5_prime_UTR	Exon 1 of 38	ENSP00000392028.1	Q9P2D1-1
CHD7	ENST00000933299.1		c.-472_-467dupGGCGGC	5_prime_UTR	Exon 1 of 38	ENSP00000603358.1
CHD7	ENST00000933298.1		c.-472_-467dupGGCGGC	5_prime_UTR	Exon 1 of 38	ENSP00000603357.1

Frequencies

GnomAD3 genomes

AF:

0.0921

AC:

12663

AN:

137510

Hom.:

801

Cov.:

show subpopulations

Gnomad AFR

AF:

0.142

Gnomad AMI

AF:

0.0401

Gnomad AMR

AF:

0.0550

Gnomad ASJ

AF:

0.0675

Gnomad EAS

AF:

0.197

Gnomad SAS

AF:

0.110

Gnomad FIN

AF:

0.0464

Gnomad MID

AF:

0.102

Gnomad NFE

AF:

0.0699

Gnomad OTH

AF:

0.0734

GnomAD4 exome

AF:

0.0686

AC:

AN:

612

Hom.:

Cov.:

AF XY:

0.0514

AC XY:

AN XY:

350

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.0850

AC:

AN:

400

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0361

AC:

AN:

194

Other (OTH)

AF:

0.167

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000535577), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.399

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:

0.0921

AC:

12665

AN:

137504

Hom.:

801

Cov.:

AF XY:

0.0913

AC XY:

6085

AN XY:

66660

show subpopulations

African (AFR)

AF:

0.142

AC:

5347

AN:

37704

American (AMR)

AF:

0.0549

AC:

782

AN:

14240

Ashkenazi Jewish (ASJ)

AF:

0.0675

AC:

223

AN:

3306

East Asian (EAS)

AF:

0.197

AC:

872

AN:

4428

South Asian (SAS)

AF:

0.111

AC:

492

AN:

4434

European-Finnish (FIN)

AF:

0.0464

AC:

342

AN:

7364

Middle Eastern (MID)

AF:

0.100

AC:

AN:

260

European-Non Finnish (NFE)

AF:

0.0699

AC:

4406

AN:

63028

Other (OTH)

AF:

0.0745

AC:

141

AN:

1892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

529

1059

1588

2118

2647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<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:

0.0548

Hom.:

1058

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

CHARGE syndrome (2)

Hypogonadism with anosmia (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.40

Splicing

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over