8-60741901-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_017780.4(CHD7):c.469C>T(p.Arg157*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CHD7
NM_017780.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 1.18

Publications

6 publications found

Variant links:

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

CHD7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-60741901-C-T is Pathogenic according to our data. Variant chr8-60741901-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 195321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD7	NM_017780.4 link	c.469C>T	p.Arg157*	stop_gained	Exon 2 of 38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7 link	c.469C>T	p.Arg157*	stop_gained	Exon 2 of 38	5	NM_017780.4	ENSP00000392028.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000407

AC:

AN:

245594

AF XY:

0.00000749

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000900

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460796

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726616

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86156

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111552

Other (OTH)

AF:

0.00

AC:

AN:

60312

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000161

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CHARGE syndrome

Pathogenic:6

Sep 05, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 18, 2021

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 10, 2018

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

May 13, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PVS1 very strong, PS4 moderate, PM2 moderate, PM6 strong, PP1 -

Jul 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg157*) in the CHD7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHD7 are known to be pathogenic (PMID: 22461308, 25077900). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with CHARGE syndrome (PMID: 15300250, 16155193, 17661815, 20624498, 21158681, 22461308, 23024289, 26538304; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 195321). For these reasons, this variant has been classified as Pathogenic. -

Apr 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PS2, PM2 -

not provided

Pathogenic:2

Jul 22, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 17, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21554267, 21856375, 16155193, 21158681, 22461308, 17661815, 20624498, 21378379, 15300250, 26538304, 23024289) -

not specified

Pathogenic:1

Feb 17, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Nov 04, 2016

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R157* variant (also known as c.469C>T), located in coding exon 1 of the CHD7 gene, results from a C to T substitution at nucleotide position 469. This changes the amino acid from an arginine to a stop codon within coding exon 1. This mutation has been detected in several individuals with CHARGE syndrome diagnoses and in others who only presented with minor diagnostic criteria features (Sohn YB et al. J. Hum. Genet., 2016 Mar;61:235-9). (Vissers LE et al. Nat. Genet., 2004 Sep;36:955-7). (Delahaye A et al. Clin. Genet., 2007 Aug;72:112-21). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

CHD7-related disorder

Pathogenic:1

Jun 26, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CHD7 c.469C>T variant is predicted to result in premature protein termination (p.Arg157*). This variant has been previously reported in the heterozygous state in several individuals with CHARGE syndrome (see, for example, Vissers et al. 2004. PubMed ID: 15300250, reported as R157X; Sohn et al. 2015. PubMed ID: 26538304). It has been reported as both a de novo variant (Legendre et al. 2012. PubMed ID: 23024289), and an inherited variant characterized by intrafamilial clinical variability (Delahaye et al. 2007. PubMed ID: 17661815). This variant is reported in 0.00090% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in CHD7 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Benign

0.69

PhyloP100

1.2

Vest4

0.88

GERP RS

4.3

PromoterAI

0.014

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over