rs1554597716

Positions:

• chr8-60822651-C-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.3106C>T​(p.Arg1036*) 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:5
• Conservation: PhyloP100: 2.59

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 8-60822651-C-T is Pathogenic according to our data. Variant chr8-60822651-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 488373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD7	NM_017780.4	c.3106C>T	p.Arg1036*	stop_gained	12/38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.3106C>T	p.Arg1036*	stop_gained	12/38	5	NM_017780.4	ENSP00000392028.1
CHD7	ENST00000524602.5	c.1717-39578C>T		intron_variant		1		ENSP00000437061.1
CHD7	ENST00000525508.1	c.3106C>T	p.Arg1036*	stop_gained	11/12	5		ENSP00000436027.1
CHD7	ENST00000695853.1	n.3106C>T		non_coding_transcript_exon_variant	12/37			ENSP00000512218.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHARGE syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	In-silico prediction tools (MutationTaster and CADD phred) are consistent in predicting the variant to be damaging to CHD7 protein function. This variant is predicted to cause premature termination of the transcript, which will either lead to the nonsense-mediated mRNA decay or formation of a truncated protein product. This variant has also been reported in individuals affected with CHARGE syndrome (ClinVar ID-488373; Moccia et al., 2018). The clinical features in the proband overlap with CHARGE syndrome. -
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	Centre for Translational Omics - GOSgene, University College London	Mar 16, 2018	- -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 08, 2022

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: 16155193, 29300383, 33502061, 22462537, 21158681, 25525159, 16615981, 30498854, 23024289, 30049826, 34134972) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.92	D
Vest4		0.88
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554597716; hg19: chr8-61735210; COSMIC: COSV71115240;