Genetic Variant CHD7:c.-478_-467dupGGCGGCGGCGGC (chr8-60678764-C-CGCGGCGGCGGCG) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_017780.4(CHD7):c.-478_-467dupGGCGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0059 ( 13 hom., cov: 0)

Exomes 𝑓: 0.0016 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CHD7
NM_017780.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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: 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 -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00586 (806/137566) while in subpopulation AFR AF = 0.0104 (392/37726). AF 95% confidence interval is 0.00954. There are 13 homozygotes in GnomAd4. There are 413 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD7	NM_017780.4 link	c.-478_-467dupGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 38	ENST00000423902.7	NP_060250.2	Q9P2D1-1Q6ZWF9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7 link	c.-478_-467dupGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 38	5	NM_017780.4	ENSP00000392028.1		Q9P2D1-1

Frequencies

GnomAD3 genomes

AF:

0.00586

AC:

806

AN:

137572

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00780

Gnomad ASJ

AF:

0.000605

Gnomad EAS

AF:

0.00763

Gnomad SAS

AF:

0.00784

Gnomad FIN

AF:

0.000271

Gnomad MID

AF:

0.00352

Gnomad NFE

AF:

0.00343

Gnomad OTH

AF:

0.00744

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00163

AC:

AN:

614

Hom.:

Cov.:

AF XY:

0.00284

AC XY:

AN XY:

352

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:

0.00249

AC:

AN:

402

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

194

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00586

AC:

806

AN:

137566

Hom.:

Cov.:

AF XY:

0.00619

AC XY:

413

AN XY:

66694

show subpopulations

African (AFR)

AF:

0.0104

AC:

392

AN:

37726

American (AMR)

AF:

0.00772

AC:

110

AN:

14242

Ashkenazi Jewish (ASJ)

AF:

0.000605

AC:

AN:

3308

East Asian (EAS)

AF:

0.00767

AC:

AN:

4434

South Asian (SAS)

AF:

0.00789

AC:

AN:

4436

European-Finnish (FIN)

AF:

0.000271

AC:

AN:

7368

Middle Eastern (MID)

AF:

0.00385

AC:

AN:

260

European-Non Finnish (NFE)

AF:

0.00343

AC:

216

AN:

63048

Other (OTH)

AF:

0.00739

AC:

AN:

1894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00206

Hom.:

1058

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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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8-60678764-CGCGGCGGCGGCGGCGGCGGCG-CGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

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