rs141947938

chr8-60795119-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017780.4(CHD7):c.2230G>A(p.Gly744Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000758 in 1,612,560 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G744G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0043 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 7.99

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CHD7
• BP4: Computational evidence support a benign effect (MetaRNN=0.008596957).
• BP6: Variant 8-60795119-G-A is Benign according to our data. Variant chr8-60795119-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 158282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60795119-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00433 (659/152248) while in subpopulation AFR AF= 0.0153 (634/41530). AF 95% confidence interval is 0.0143. There are 3 homozygotes in gnomad4. There are 293 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 659 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.2230G>A	p.Gly744Ser	missense_variant	4/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.2230G>A	p.Gly744Ser	missense_variant	4/38	5	NM_017780.4	P1

Frequencies

GnomAD3 genomes AF: 0.00433 AC: 659 AN: 152130 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00104 AC: 257 AN: 247686 Hom.: 0 AF XY: 0.000662 AC XY: 89 AN XY: 134386

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.000908

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.000501

GnomAD4 exome AF: 0.000386 AC: 564 AN: 1460312 Hom.: 2 Cov.: 31 AF XY: 0.000325 AC XY: 236 AN XY: 726388

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.000832

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.000995

GnomAD4 genome AF: 0.00433 AC: 659 AN: 152248 Hom.: 3 Cov.: 32 AF XY: 0.00394 AC XY: 293 AN XY: 74430

Gnomad4 AFR AF: 0.0153

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000729 Hom.: 2

Bravo AF: 0.00474

ESP6500AA AF: 0.0123 AC: 45

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00128 AC: 154

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000547

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

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	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 25, 2024	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 22, 2019	The p.Gly744Ser variant in CHD7 is classified as benign because it has been identified in 1.5% (364/24154) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP criteria applied: BA1. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 28, 2014	- -

CHARGE syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign, for CHARGE syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BS4 => Lack of segregation in affected members of a family. (PMID:21995344). -
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 01, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2018

This variant is associated with the following publications: (PMID: 25077900, 23891399, 21995344, 22539353) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.067	T;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.59	T;T
MetaRNN	Benign	0.0086	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.090	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.30	T;T
Sift4G	Benign	0.98	T;T
Polyphen		1.0	D;.
Vest4		0.76
MVP		0.84
MPC		0.52
ClinPred		0.019	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs141947938; hg19: chr8-61707678;