8-60678791-A-AGCG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_017780.4(CHD7):c.-447_-445dup 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 867 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.-447_-445dup		5_prime_UTR_variant	1/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.-447_-445dup		5_prime_UTR_variant	1/38	5	NM_017780.4	P1
CHD7	ENST00000695848.1	n.67_69dup		non_coding_transcript_exon_variant	1/7
CHD7	ENST00000695849.1	n.67_69dup		non_coding_transcript_exon_variant	1/7
CHD7	ENST00000695853.1	c.-447_-445dup		5_prime_UTR_variant, NMD_transcript_variant	1/37

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00295

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00147

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.0372

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00967

Gnomad4 EAS AF: 0.0441

Gnomad4 SAS AF: 0.00656

Gnomad4 FIN AF: 0.00128

Gnomad4 NFE AF: 0.00761

Gnomad4 OTH AF: 0.0127

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

CHARGE syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypogonadism with anosmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs71245513; hg19: chr8-61591350;