rs377139749

Positions:

• chr8-60781383-G-GAAAGCA

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM4 PP3 BP6_Very_Strong BS1 BS2

The NM_017780.4(CHD7):​c.2053_2058dup​(p.Ala685_Lys686dup) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00989 in 1,539,622 control chromosomes in the GnomAD database, including 75 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (6 hom., cov: 32)
  • Exomes 𝑓: 0.010 (69 hom.)
• Consequence: CHD7 NM_017780.4 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 8.03

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 -13 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_017780.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 8-60781383-G-GAAAGCA is Benign according to our data. Variant chr8-60781383-G-GAAAGCA is described in ClinVar as [Likely_benign]. Clinvar id is 95776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00772 (1175/152290) while in subpopulation NFE AF= 0.0119 (811/68030). AF 95% confidence interval is 0.0112. There are 6 homozygotes in gnomad4. There are 573 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1175 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD7	NM_017780.4	c.2053_2058dup	p.Ala685_Lys686dup	inframe_insertion	3/38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.2053_2058dup	p.Ala685_Lys686dup	inframe_insertion	3/38	5	NM_017780.4	ENSP00000392028	P1

Frequencies

GnomAD3 genomes AF: 0.00772 AC: 1175 AN: 152172 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00623 AC: 960 AN: 154032 Hom.: 5 AF XY: 0.00569 AC XY: 471 AN XY: 82834

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.00752

Gnomad ASJ exome AF: 0.00432

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000617

Gnomad FIN exome AF: 0.00299

Gnomad NFE exome AF: 0.00979

Gnomad OTH exome AF: 0.00659

GnomAD4 exome AF: 0.0101 AC: 14049 AN: 1387332 Hom.: 69 Cov.: 32 AF XY: 0.00985 AC XY: 6752 AN XY: 685424

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00713

Gnomad4 ASJ exome AF: 0.00531

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.00351

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.00911

GnomAD4 genome AF: 0.00772 AC: 1175 AN: 152290 Hom.: 6 Cov.: 32 AF XY: 0.00770 AC XY: 573 AN XY: 74458

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.0100

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00302

Gnomad4 NFE AF: 0.0119

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00979 Hom.: 9

Bravo AF: 0.00841

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
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	Eurofins Ntd Llc (ga)	Dec 06, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 10, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2018	p.Ala685_Lys686dup (c.2053_2058dupGCAAAA) in exon 3 of CHD7: This variant is cla ssified as benign because it has been identified in 1% of European chromosomes, including 4 homozygotes, by the Genome Aggregation Database (gnomAD; http://gnom ad.broadinstitute.org; dbSNP rs377139749). ACMG/AMP Criteria applied: BA1. -

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2016	This variant is associated with the following publications: (PMID: 29304373, 28475860, 25077900) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CHD7: PM4, BS1, BS2 -

CHARGE syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 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. -

Hypogonadism with anosmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs377139749; hg19: chr8-61693942;