rs147994149

chr8-60823835-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017780.4(CHD7):c.3202-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,612,494 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (32 hom.)
• Consequence: CHD7 NM_017780.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001421
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.662

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=-0.74).
• BP6: Variant 8-60823835-T-C is Benign according to our data. Variant chr8-60823835-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 95784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60823835-T-C is described in Lovd as [Benign]. Variant chr8-60823835-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00117 (179/152358) while in subpopulation EAS AF= 0.0281 (146/5188). AF 95% confidence interval is 0.0244. There are 5 homozygotes in gnomad4. There are 102 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 179 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.3202-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.3202-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_017780.4	P1
CHD7	ENST00000524602.5	c.1717-38394T>C		intron_variant		1
CHD7	ENST00000525508.1	c.3202-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
CHD7	ENST00000695853.1	c.3202-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152240 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0279

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00222 AC: 551 AN: 247974 Hom.: 6 AF XY: 0.00218 AC XY: 294 AN XY: 134690

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.0266

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000143

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00121 AC: 1774 AN: 1460136 Hom.: 32 Cov.: 30 AF XY: 0.00124 AC XY: 898 AN XY: 726460

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00146

Gnomad4 EAS exome AF: 0.0352

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00117 AC: 179 AN: 152358 Hom.: 5 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74516

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0281

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000447 Hom.: 0

Bravo AF: 0.00153

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000238

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 26, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

CHARGE syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	- -

not provided Benign:2

Likely 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	GeneDx	Dec 24, 2018	This variant is associated with the following publications: (PMID: 32369273, 22461308, 24416387, 23341491, 25472840, 19065520, 25525159, 23533228) -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CHARGE syndrome;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 27, 2021

- -

Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	7.0
Dann	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
SpliceAI score (max)		0.020		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: rs147994149; hg19: chr8-61736394; COSMIC: COSV71115576;