rs3763592

Positions:

• chr8-60852714-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017780.4(CHD7):​c.6103+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0572 in 1,613,390 control chromosomes in the GnomAD database, including 7,029 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (3121 hom., cov: 32)
  • Exomes 𝑓: 0.049 (3908 hom.)
• Consequence: CHD7 NM_017780.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002795
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0930

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-60852714-C-T is Benign according to our data. Variant chr8-60852714-C-T is described in ClinVar as [Benign]. Clinvar id is 95799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60852714-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.6103+8C>T		splice_region_variant, intron_variant		ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.6103+8C>T		splice_region_variant, intron_variant		5	NM_017780.4	P1
CHD7	ENST00000524602.5	c.1717-9515C>T		intron_variant		1
CHD7	ENST00000695853.1	c.6103+8C>T		splice_region_variant, intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20950 AN: 151966 Hom.: 3120 Cov.: 32

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0711

Gnomad ASJ AF: 0.0688

Gnomad EAS AF: 0.0164

Gnomad SAS AF: 0.0478

Gnomad FIN AF: 0.0757

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0411

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.0662 AC: 16489 AN: 249032 Hom.: 1462 AF XY: 0.0611 AC XY: 8257 AN XY: 135124

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.0398

Gnomad ASJ exome AF: 0.0749

Gnomad EAS exome AF: 0.0132

Gnomad SAS exome AF: 0.0465

Gnomad FIN exome AF: 0.0806

Gnomad NFE exome AF: 0.0411

Gnomad OTH exome AF: 0.0589

GnomAD4 exome AF: 0.0488 AC: 71363 AN: 1461306 Hom.: 3908 Cov.: 32 AF XY: 0.0476 AC XY: 34633 AN XY: 726954

Gnomad4 AFR exome AF: 0.385

Gnomad4 AMR exome AF: 0.0446

Gnomad4 ASJ exome AF: 0.0755

Gnomad4 EAS exome AF: 0.0166

Gnomad4 SAS exome AF: 0.0475

Gnomad4 FIN exome AF: 0.0783

Gnomad4 NFE exome AF: 0.0371

Gnomad4 OTH exome AF: 0.0643

GnomAD4 genome AF: 0.138 AC: 20973 AN: 152084 Hom.: 3121 Cov.: 32 AF XY: 0.137 AC XY: 10165 AN XY: 74350

Gnomad4 AFR AF: 0.373

Gnomad4 AMR AF: 0.0710

Gnomad4 ASJ AF: 0.0688

Gnomad4 EAS AF: 0.0162

Gnomad4 SAS AF: 0.0473

Gnomad4 FIN AF: 0.0757

Gnomad4 NFE AF: 0.0410

Gnomad4 OTH AF: 0.119

Alfa AF: 0.0560 Hom.: 1267

Bravo AF: 0.145

Asia WGS AF: 0.0490 AC: 172 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 21, 2017	c.6103+8C>T in intron 30 of CHD7: This variant is not expected to have clinical significance because it has been identified in 38.25% (9168/23972) of African ch romosomes including 1772 homozygotes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs3763592). ACMG/AMP criteria applied: BA1. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 22033296, 27884173, 16400610, 21158681) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CHARGE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.1
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
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: rs3763592; hg19: chr8-61765273;