rs41272435

chr8-60741739-T-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.307T>A(p.Ser103Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0179 in 1,613,918 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S103L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (12 hom., cov: 32)
  • Exomes 𝑓: 0.018 (258 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 3.98

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=0.008754194).
• BP6: Variant 8-60741739-T-A is Benign according to our data. Variant chr8-60741739-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 95782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60741739-T-A is described in Lovd as [Benign]. Variant chr8-60741739-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.013 (1984/152274) while in subpopulation NFE AF= 0.0191 (1298/68012). AF 95% confidence interval is 0.0182. There are 12 homozygotes in gnomad4. There are 959 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1984 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.307T>A	p.Ser103Thr	missense_variant	2/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.307T>A	p.Ser103Thr	missense_variant	2/38	5	NM_017780.4	P1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1984 AN: 152156 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00439

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0191

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0123 AC: 3064 AN: 249020 Hom.: 31 AF XY: 0.0124 AC XY: 1672 AN XY: 135120

Gnomad AFR exome AF: 0.00330

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00288

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.0185

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0184 AC: 26845 AN: 1461644 Hom.: 258 Cov.: 32 AF XY: 0.0179 AC XY: 12994 AN XY: 727096

Gnomad4 AFR exome AF: 0.00263

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0144

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00266

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.0216

Gnomad4 OTH exome AF: 0.0168

GnomAD4 genome AF: 0.0130 AC: 1984 AN: 152274 Hom.: 12 Cov.: 32 AF XY: 0.0129 AC XY: 959 AN XY: 74468

Gnomad4 AFR AF: 0.00438

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.0185

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0156

Gnomad4 NFE AF: 0.0191

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0171 Hom.: 11

Bravo AF: 0.0134

TwinsUK AF: 0.0205 AC: 76

ALSPAC AF: 0.0275 AC: 106

ESP6500AA AF: 0.00486 AC: 21

ESP6500EA AF: 0.0170 AC: 145

ExAC AF: 0.0115 AC: 1399

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0207

EpiControl AF: 0.0197

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Ser103Thr in exon 2 of CHD7: This variant is not expected to have clinical sig nificance because it has been identified in 1.70% (1123/66212) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs41272435). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely 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	Sep 29, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 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

Oct 20, 2021

- -

Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.82	T;T;T
MetaRNN	Benign	0.0088	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.063
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.039	D;T;T
Polyphen		0.38	B;.;.
Vest4		0.32
MPC		0.14
ClinPred		0.0094	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.68

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: rs41272435; hg19: chr8-61654298;