chr8-60678764-CGCG-C

Variant names:

• chr8-60678764-CGCG-C
• rs886063023
• NM_017780.4:c.-469_-467delGGC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_017780.4(CHD7):​c.-469_-467delGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 138,180 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 0)
  • Exomes 𝑓: 0.013 (0 hom.)
• Consequence: CHD7 NM_017780.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.88
• Publications: 2 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000196 (27/137578) while in subpopulation AFR AF = 0.000557 (21/37734). AF 95% confidence interval is 0.000373. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.-469_-467delGGC		5_prime_UTR	Exon 1 of 38	NP_060250.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD7	ENST00000423902.7	TSL:5 MANE Select	c.-469_-467delGGC		5_prime_UTR	Exon 1 of 38	ENSP00000392028.1	Q9P2D1-1
	CHD7	ENST00000933299.1		c.-469_-467delGGC		5_prime_UTR	Exon 1 of 38	ENSP00000603358.1
	CHD7	ENST00000933298.1		c.-469_-467delGGC		5_prime_UTR	Exon 1 of 38	ENSP00000603357.1

Frequencies

GnomAD3 genomes AF: 0.000196 AC: 27 AN: 137584 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000557

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: 0.000136

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000793

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0133 AC: 8 AN: 602 Hom.: 0 AF XY: 0.0174 AC XY: 6 AN XY: 344

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

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 4

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00505 AC: 2 AN: 396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0319 AC: 6 AN: 188

Other (OTH) AF: 0.00 AC: 0 AN: 6

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000182668), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000196 AC: 27 AN: 137578 Hom.: 0 Cov.: 0 AF XY: 0.000195 AC XY: 13 AN XY: 66696

African (AFR) AF: 0.000557 AC: 21 AN: 37734

American (AMR) AF: 0.00 AC: 0 AN: 14242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3308

East Asian (EAS) AF: 0.00 AC: 0 AN: 4434

South Asian (SAS) AF: 0.00 AC: 0 AN: 4438

European-Finnish (FIN) AF: 0.000136 AC: 1 AN: 7368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.0000793 AC: 5 AN: 63050

Other (OTH) AF: 0.00 AC: 0 AN: 1894

Alfa AF: 0.00 Hom.: 1058

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=99/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886063023; hg19: chr8-61591323;