rs886040991

Variant names:

• chr8-60838115-C-T
• rs886040991
• NM_017780.4:c.4393C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017780.4(CHD7):​c.4393C>T​(p.Arg1465*) 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)
• Consequence: CHD7 NM_017780.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.48

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 Pathogenic. Variant got 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 8-60838115-C-T is Pathogenic according to our data. Variant chr8-60838115-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 267430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60838115-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD7	NM_017780.4	c.4393C>T	p.Arg1465*	stop_gained	Exon 19 of 38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.4393C>T	p.Arg1465*	stop_gained	Exon 19 of 38	5	NM_017780.4	ENSP00000392028.1
CHD7	ENST00000524602.5	c.1717-24114C>T		intron_variant	Intron 2 of 4	1		ENSP00000437061.1
CHD7	ENST00000695853.1	n.4393C>T		non_coding_transcript_exon_variant	Exon 19 of 37			ENSP00000512218.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHARGE syndrome Pathogenic:5

Mar 07, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000267430 /PMID: 16400610). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

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

- -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with CHARGE syndrome (MIM#214800). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic in individuals with CHARGE syndrome (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in patients with CHARGE syndrome (ClinVar, PMID: 16400610, PMID: 22033296). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 29, 2019

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes: PVS1, PS2, PM2, PP5 -

Nov 29, 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.Arg1465*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with CHARGE syndrome (PMID: 16400610, 22033296). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 267430). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Aug 28, 2019

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in individuals with clinical features associated with this gene. Among the reported individuals, the inheritance appeared to be de novo in multiple cases (PMID 31387071, 22033296, 16400610).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -

Jul 18, 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29304373, 25525159, 20186815, 28991257, 21158681, 16400610, 28475860, 22033296, 32368696, 33587123) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CHD7-related disorder Pathogenic:1

Nov 09, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CHD7 c.4393C>T variant is predicted to result in premature protein termination (p.Arg1465*). This variant has been previously reported in individuals with CHARGE syndrome (see for example Lalani et al. 2006. PubMed ID: 16400610; Bilan et al. 2012. PubMed ID: 22033296; Butcher et al. 2017. PubMed ID: 28475860, Table S5; Maron et al. 2021. PubMed ID: 33587123). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. 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	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.91	D
Vest4		0.93
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs886040991; hg19: chr8-61750674; COSMIC: COSV71112190;