8-60678791-A-AGCG

Variant names:

• chr8-60678791-A-AGCG
• rs71245513
• NM_017780.4:c.-447_-445dupGCG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_017780.4(CHD7):​c.-447_-445dupGCG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 50,286 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.018 (9 hom., cov: 29)
  • Exomes 𝑓: 0.0021 (0 hom.)
• Consequence: CHD7 NM_017780.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.12
• Publications: 0 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: 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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0177 (867/48848) while in subpopulation EAS AF = 0.0441 (52/1180). AF 95% confidence interval is 0.0345. There are 9 homozygotes in GnomAd4. There are 428 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD7	NM_017780.4	c.-447_-445dupGCG		5_prime_UTR_variant	Exon 1 of 38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.-447_-445dupGCG		5_prime_UTR_variant	Exon 1 of 38	5	NM_017780.4	ENSP00000392028.1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 867 AN: 48826 Hom.: 9 Cov.: 29

Gnomad AFR AF: 0.0372

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00967

Gnomad EAS AF: 0.0448

Gnomad SAS AF: 0.00649

Gnomad FIN AF: 0.00128

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00761

Gnomad OTH AF: 0.0128

GnomAD4 exome AF: 0.00209 AC: 3 AN: 1438 Hom.: 0 Cov.: 0 AF XY: 0.00261 AC XY: 2 AN XY: 766

African (AFR) AF: 0.00 AC: 0 AN: 18

American (AMR) AF: 0.00 AC: 0 AN: 10

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

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

South Asian (SAS) AF: 0.00295 AC: 2 AN: 678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.00147 AC: 1 AN: 680

Other (OTH) AF: 0.00 AC: 0 AN: 32

GnomAD4 genome AF: 0.0177 AC: 867 AN: 48848 Hom.: 9 Cov.: 29 AF XY: 0.0182 AC XY: 428 AN XY: 23568

African (AFR) AF: 0.0372 AC: 507 AN: 13630

American (AMR) AF: 0.0107 AC: 56 AN: 5248

Ashkenazi Jewish (ASJ) AF: 0.00967 AC: 13 AN: 1344

East Asian (EAS) AF: 0.0441 AC: 52 AN: 1180

South Asian (SAS) AF: 0.00656 AC: 8 AN: 1220

European-Finnish (FIN) AF: 0.00128 AC: 3 AN: 2352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 100

European-Non Finnish (NFE) AF: 0.00761 AC: 172 AN: 22598

Other (OTH) AF: 0.0127 AC: 9 AN: 710

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

CHARGE syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypogonadism with anosmia Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=299/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs71245513; hg19: chr8-61591350;