rs41305525

chr8-60742450-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017780.4(CHD7):c.1018A>G(p.Met340Val) variant causes a missense change. The variant allele was found at a frequency of 0.00619 in 1,614,006 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (33 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 4.82

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CHD7
• BP4: Computational evidence support a benign effect (MetaRNN=0.00827083).
• BP6: Variant 8-60742450-A-G is Benign according to our data. Variant chr8-60742450-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 95773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60742450-A-G is described in Lovd as [Benign]. Variant chr8-60742450-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00496 (755/152334) while in subpopulation AMR AF= 0.00915 (140/15300). AF 95% confidence interval is 0.00792. There are 4 homozygotes in gnomad4. There are 393 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 755 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.1018A>G	p.Met340Val	missense_variant	2/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.1018A>G	p.Met340Val	missense_variant	2/38	5	NM_017780.4	P1

Frequencies

GnomAD3 genomes AF: 0.00496 AC: 755 AN: 152216 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00707

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00462 AC: 1151 AN: 249288 Hom.: 4 AF XY: 0.00467 AC XY: 631 AN XY: 135248

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00359

Gnomad ASJ exome AF: 0.00944

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00712

Gnomad OTH exome AF: 0.00578

GnomAD4 exome AF: 0.00632 AC: 9236 AN: 1461672 Hom.: 33 Cov.: 32 AF XY: 0.00623 AC XY: 4533 AN XY: 727126

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00373

Gnomad4 ASJ exome AF: 0.00907

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000951

Gnomad4 FIN exome AF: 0.00225

Gnomad4 NFE exome AF: 0.00740

Gnomad4 OTH exome AF: 0.00542

GnomAD4 genome AF: 0.00496 AC: 755 AN: 152334 Hom.: 4 Cov.: 32 AF XY: 0.00528 AC XY: 393 AN XY: 74494

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00915

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00707

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00604 Hom.: 1

Bravo AF: 0.00528

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00177 AC: 7

ESP6500EA AF: 0.00745 AC: 62

ExAC AF: 0.00418 AC: 506

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00851

EpiControl AF: 0.00771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 25, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Met340Val in exon 2 of CHD7: This variant is not expected to have clinical sig nificance because it has been identified in 0.63% (422/66716) of European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs41305525). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 27, 2012	- -
Benign, flagged submission	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Sep 07, 2017	BS1, BS2, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult where full penetrance of the disorder is expected at an early age, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 03, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CHD7: BP4, BS1, BS2 -

CHARGE syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.85	T;T;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.0083	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.81	L;L;L
MutationTaster	Benign	0.90	D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.42	N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.080	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.60
MVP		0.98
MPC		0.10
ClinPred		0.010	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.44

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: rs41305525; hg19: chr8-61655009;