rs587783442

chr8-60838202-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_017780.4(CHD7):c.4480C>T(p.Arg1494Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1494R) has been classified as Likely benign. 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.13

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 8-60838202-C-T is Pathogenic according to our data. Variant chr8-60838202-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 158296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60838202-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.4480C>T	p.Arg1494Ter	stop_gained	19/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.4480C>T	p.Arg1494Ter	stop_gained	19/38	5	NM_017780.4	P1
CHD7	ENST00000524602.5	c.1717-24027C>T		intron_variant		1
CHD7	ENST00000695853.1	c.4480C>T	p.Arg1494Ter	stop_gained, NMD_transcript_variant	19/37

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450064 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719886

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHARGE syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	research	Sbielas Lab-Department of Human Genetics University of Michigan, University of Michigan Medical School	Oct 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 12, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 158296). This premature translational stop signal has been observed in individuals with CHARGE syndrome (PMID: 16615981, 18089695, 21158681). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1494*) 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). -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2017

The p.R1494* pathogenic mutation (also known as c.4480C>T), located in coding exon 18 of the CHD7 gene, results from a C to T substitution at nucleotide position 4480. This changes the amino acid from an arginine to a stop codon within coding exon 18. This mutation has been identified in multiple individuals with a clinical diagnosis of CHARGE syndrome (Aramaki M et al. J. Pediatr., 2006 Mar;148:410-4; Asakura Y et al. J. Clin. Endocrinol. Metab., 2008 Mar;93:920-4; Fujita K et al. AJNR Am J Neuroradiol, 2009 Mar;30:629-34; Bartels CF et al. Genet Test Mol Biomarkers, 2010 Dec;14:881-91). 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2018

The R1494X nonsense variant in the CHD7 gene has been reported previously in association with CHARGE syndrome (Aramaki et al., 2006). The variant is not observed in large population cohorts (Lek et al., 2016). Approximately 45% of CHD7 pathogenic variants are nonsense changes predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay (Janssen et al., 2012; Zentner et al, 2010). In summary, we consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	38
Dann	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	A;A;D
Vest4		0.93
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs587783442; hg19: chr8-61750761;