rs192129249

chr8-60856859-A-Cchr8-60856859-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.7579A>C(p.Met2527Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00428 in 1,566,236 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (23 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:16
• Conservation: PhyloP100: 4.93

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=0.011278272).
• BP6: Variant 8-60856859-A-C is Benign according to our data. Variant chr8-60856859-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 158317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60856859-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00257 (392/152322) while in subpopulation NFE AF= 0.00459 (312/68016). AF 95% confidence interval is 0.00417. There are 0 homozygotes in gnomad4. There are 148 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 392 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.7579A>C	p.Met2527Leu	missense_variant	34/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.7579A>C	p.Met2527Leu	missense_variant	34/38	5	NM_017780.4	P1

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 392 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00459

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00203 AC: 426 AN: 210028 Hom.: 1 AF XY: 0.00206 AC XY: 233 AN XY: 113160

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.000459

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000465

Gnomad FIN exome AF: 0.000261

Gnomad NFE exome AF: 0.00363

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00446 AC: 6304 AN: 1413914 Hom.: 23 Cov.: 32 AF XY: 0.00433 AC XY: 3027 AN XY: 698764

Gnomad4 AFR exome AF: 0.000827

Gnomad4 AMR exome AF: 0.00129

Gnomad4 ASJ exome AF: 0.000432

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000511

Gnomad4 FIN exome AF: 0.000503

Gnomad4 NFE exome AF: 0.00548

Gnomad4 OTH exome AF: 0.00372

GnomAD4 genome AF: 0.00257 AC: 392 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.00199 AC XY: 148 AN XY: 74498

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00459

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00264 Hom.: 2

Bravo AF: 0.00254

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00119 AC: 5

ESP6500EA AF: 0.00508 AC: 43

ExAC AF: 0.00196 AC: 237

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2019	This variant is associated with the following publications: (PMID: 27884859, 30921766, 25077900, 21158681, 25996639, 29891883) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CHD7: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 04, 2018	The p.Met2527Leu variant in CHD7 is classified as benign because it has been ide ntified in 0.36% (407/113196) of European chromosomes, including 1 homozygous in dividual, by gnomAD (http://gnomad.broadinstitute.org) and due to a lack of cons ervation across species, including mammals. Of note, four mammals have a leucine (Leu) at this position despite high nearby amino acid conservation. In addition , computational prediction tools do not suggest a high likelihood of impact to t he protein. Finally, although this variant has been reported in individuals with CHARGE syndrome, it was also identified in their unaffected parents (Bartels 20 10, Marcos 2014). ACMG/AMP Criteria applied: BA1, BP4_Strong, BS4. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2014	- -

Hypogonadotropic hypogonadism 5 with or without anosmia Benign:2

Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign, for Hypogonadotropic hypogonadism 5 with or without anosmia, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS4 => Lack of segregation in affected members of a family (PMID:25077900). BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -
Benign, 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 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. -

CHARGE association Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Amenorrhea Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Mar 08, 2021

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2017

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. -

CHARGE association;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 10, 2022

- -

CHD7-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	15
Dann	Benign	0.48
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.88	L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.36		Loss of MoRF binding (P = 0.0749);
MVP		0.56
MPC		0.17
ClinPred		0.0050	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.073
gMVP		0.42

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: rs192129249; hg19: chr8-61769418;