NM_017780.4:c.-466A>G

Variant names:

• chr8-60678791-A-G
• rs71513464
• NM_017780.4:c.-466A>G

Variant summary

Our verdict is Benign. The variant received -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
• 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
CHD7	NM_017780.4	c.-466A>G		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.-466A>G		5_prime_UTR_variant	Exon 1 of 38	5	NM_017780.4	ENSP00000392028.1

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

African (AFR) AF: 0.0625 AC: 1 AN: 16

American (AMR) AF: 0.00 AC: 0 AN: 8

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

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

South Asian (SAS) AF: 0.0240 AC: 16 AN: 666

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

Middle Eastern (MID) AF: 0.250 AC: 2 AN: 8

European-Non Finnish (NFE) AF: 0.0285 AC: 19 AN: 666

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

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

African (AFR) AF: 0.227 AC: 3092 AN: 13594

American (AMR) AF: 0.125 AC: 657 AN: 5242

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 141 AN: 1344

East Asian (EAS) AF: 0.152 AC: 179 AN: 1180

South Asian (SAS) AF: 0.161 AC: 196 AN: 1214

European-Finnish (FIN) AF: 0.0332 AC: 78 AN: 2348

Middle Eastern (MID) AF: 0.0900 AC: 9 AN: 100

European-Non Finnish (NFE) AF: 0.0692 AC: 1563 AN: 22580

Other (OTH) AF: 0.113 AC: 80 AN: 710

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hypogonadotropic hypogonadism 5 with or without anosmia Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.71
PromoterAI		-0.040	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

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