rs398124321

Variant names:

• chr8-60850486-G-A
• rs398124321
• NM_017780.4:c.5405-7G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-60850486-G-A
• chr8-60850486-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_017780.4(CHD7):​c.5405-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CHD7 NM_017780.4 splice_region, intron
• Scores: Splicing: ADA: 0.9358
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 0.922

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-60850486-G-A is Pathogenic according to our data. Variant chr8-60850486-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 95795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60850486-G-A is described in Lovd as [Pathogenic]. Variant chr8-60850486-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD7	NM_017780.4	c.5405-7G>A		splice_region_variant, intron_variant	Intron 25 of 37	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.5405-7G>A		splice_region_variant, intron_variant	Intron 25 of 37	5	NM_017780.4	ENSP00000392028.1
CHD7	ENST00000524602.5	c.1717-11743G>A		intron_variant	Intron 2 of 4	1		ENSP00000437061.1
CHD7	ENST00000695853.1	n.5405-7G>A		splice_region_variant, intron_variant	Intron 25 of 36			ENSP00000512218.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1449966 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718616

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: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHARGE syndrome Pathogenic:11

Dec 11, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CHD7 c.5405-7G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. One computational tool predicts that the variant creates a cryptic 3 acceptor site. Two independent mini-gene assays confirm the impact on splicing, specificaly the introduction of a 5-bp intronic sequence by activation of a cryptic acceptor site leading to a frameshift mutation (Legendre_2018, Song_2011). The variant was absent in 275496 control chromosomes (gnomAD). The variant, c.5405-7G>A, has been reported in the literature in multiple individuals affected with CHARGE Syndrome (Vissers_2004, Bilan_2012, Janssen_2012, Song_2011, Legendre_2018). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

May 05, 2017

Laboratoire de Genetique Biologique, CHU de Poitiers

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: in vitro

found de novo on several CHARGE syndrome patients. Minigene assays confirm the use of a new acceptor splice site leading to frameshift in exon 26 -

Dec 20, 2016

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS2,PS3,PM2,PP3,PP4,PP5 -

Jan 14, 2019

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 08, 2017

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 25 of the CHD7 gene. It does not directly change the encoded amino acid sequence of the CHD7 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with CHARGE syndrome (PMID: 15300250, 16155193, 16615981, 21158681, 21931733, 22033296). In at least one individual the variant was observed to be de novo. This variant is also known as IVS25-7G>A and IVS26-7G>A. ClinVar contains an entry for this variant (Variation ID: 95795). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21931733). For these reasons, this variant has been classified as Pathogenic. -

-

Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

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. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21931733). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.98). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 15300250 , 22033296 ) and observed in multiple (>3) similarly affected unrelated individuals (PMID: 16155193 , 16615981 , 21158681 , 21931733). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000095795). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:6

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published in vitro splicing assay and RT-PCR studies indicate this variant creates a new splice acceptor site in intron 25 that results in abnormal gene splicing resulting in a frameshift in the resultant product (Song et al., 2011; Legendre et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 30216942, 30587507, 31130284, 21931733, 21158681, 16155193, 29255276, 22033296, 15300250, 32763379, 34008892, 32969205, 16615981) -

Jul 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

May 16, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5405-7G>A intronic pathogenic mutation results from a G to A substitution 7 nucleotides upstream from coding exon 25 in the CHD7 gene. This mutation has been reported in multiple individuals with a clinical diagnosis of CHARGE syndrome, including one de novo occurrence (Vissers LE, et al. Nat. Genet. 2004 Sep; 36(9):955-7; Jongmans MC, et al. J. Med. Genet. 2006 Apr; 43(4):306-14; Aramaki M, et al. J. Pediatr. 2006 Mar; 148(3):410-4; Song MH, et al. PLoS ONE. 2011; 6(9):e24511). In addition, an in vitro splicing analysis demonstrated the introduction of 5 additional nucleotides due to the activation of a cryptic acceptor site (Song MH, et al. PLoS ONE. 2011; 6(9):e24511). Based on the supporting evidence, c.5405-7G>A is interpreted as a disease-causing mutation. -

CHD7-related disorder Pathogenic:1

Jun 16, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CHD7 c.5405-7G>A variant is predicted to interfere with splicing. This is a well-documented recurrent pathogenic variant causative for CHARGE syndrome and has previously been reported as de novo (Bilan et al. 2012. PubMed ID: 22033296; Song et al. 2011. PubMed ID: 21931733). Functional studies found it creates a frameshift and premature protein termination by activating a cryptic splice acceptor site and introducing a five-base pair intronic sequence to the CHD7 messenger RNA (Song et al. 2011. PubMed ID: 21931733; Legendre et al. 2018. PubMed ID: 29255276). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Hypogonadotropic hypogonadism 5 with or without anosmia Pathogenic:1

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous c.5405-7G>A variant in CHD7 was identified by our study in one individual with hypogonadotropic hypogonadism with or without anosmia. Trio exome analysis showed this variant to be de novo and there are multiple reports of de novo inheritance in the literature (PMID: 15300250, 22033296). This variant was absent from large population studies and has been reported in ClinVar (Variation ID: 95795). In vitro functional studies provide some evidence that the c.5405-7G>A variant may impact protein function by causing a five base pair insertion during in vitro splicing (PMID: 21931733). However, these types of assays may not accurately represent biological function. In summary, the c.5405-7G>A variant is pathogenic based off of our findings and multiple de novo reports in the literature. ACMG/AMP Criteria applied: PM2, PS2, PM6_Strong, PS3_Moderate (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	22
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: 2
DS_AL_spliceai		0.20		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398124321; hg19: chr8-61763045; COSMIC: COSV101418202; COSMIC: COSV101418202;