8-60678791-A-G

Position:

• chr8-60678791-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017780.4(CHD7):​c.-466A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (177 hom., cov: 0)
  • Exomes 𝑓: 0.027 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHD7 NM_017780.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.706

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.-466A>G		5_prime_UTR_variant	1/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.-466A>G		5_prime_UTR_variant	1/38	5	NM_017780.4	P1
CHD7	ENST00000695848.1	n.48A>G		non_coding_transcript_exon_variant	1/7
CHD7	ENST00000695849.1	n.48A>G		non_coding_transcript_exon_variant	1/7
CHD7	ENST00000695853.1	c.-466A>G		5_prime_UTR_variant, NMD_transcript_variant	1/37

Frequencies

GnomAD3 genomes AF: 0.124 AC: 6058 AN: 48756 Hom.: 176 Cov.: 0

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.0849

Gnomad NFE AF: 0.0692

Gnomad OTH AF: 0.112

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0270 AC: 38 AN: 1408 Hom.: 5 Cov.: 0 AF XY: 0.0267 AC XY: 20 AN XY: 748

Gnomad4 AFR exome AF: 0.0625

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0285

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.124 AC: 6066 AN: 48778 Hom.: 177 Cov.: 0 AF XY: 0.125 AC XY: 2939 AN XY: 23546

Gnomad4 AFR AF: 0.227

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.161

Gnomad4 FIN AF: 0.0332

Gnomad4 NFE AF: 0.0692

Gnomad4 OTH AF: 0.113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hypogonadotropic hypogonadism 5 with or without anosmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs71513464; hg19: chr8-61591350; COSMIC: COSV71111045; COSMIC: COSV71111045;