rs184814820

Positions:

chr8-60865889-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_017780.4(CHD7):c.8950C>T(p.Leu2984Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00447 in 1,610,460 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0046 ( 26 hom. )

Consequence

CHD7
NM_017780.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 4.31

Variant links:

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]

CHD7 links:

CHD7 (HGNC:):

CHD7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CHD7. . Gene score misZ 3.2193 (greater than the threshold 3.09). Trascript score misZ 3.9401 (greater than threshold 3.09). GenCC has associacion of gene with Kallmann syndrome, hypogonadotropic hypogonadism 5 with or without anosmia, CHARGE syndrome, hypogonadotropic hypogonadism, Omenn syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.004713297).

BP6

Variant 8-60865889-C-T is Benign according to our data. Variant chr8-60865889-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60865889-C-T is described in Lovd as [Benign]. Variant chr8-60865889-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00336 (512/152320) while in subpopulation NFE AF= 0.00478 (325/68028). AF 95% confidence interval is 0.00435. There are 2 homozygotes in gnomad4. There are 267 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 512 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD7	NM_017780.4 linkuse as main transcript	c.8950C>T	p.Leu2984Phe	missense_variant	38/38	ENST00000423902.7	NP_060250.2	Q9P2D1-1Q6ZWF9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7 linkuse as main transcript	c.8950C>T	p.Leu2984Phe	missense_variant	38/38	5	NM_017780.4	ENSP00000392028.1		Q9P2D1-1

Frequencies

GnomAD3 genomes

AF:

0.00336

AC:

512

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0130

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00478

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00393

AC:

950

AN:

241832

Hom.:

AF XY:

0.00370

AC XY:

486

AN XY:

131216

show subpopulations

Gnomad AFR exome

AF:

0.000612

Gnomad AMR exome

AF:

0.000178

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00933

Gnomad NFE exome

AF:

0.00657

Gnomad OTH exome

AF:

0.00306

GnomAD4 exome

AF:

0.00459

AC:

6689

AN:

1458140

Hom.:

Cov.:

AF XY:

0.00441

AC XY:

3196

AN XY:

724972

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000234

Gnomad4 FIN exome

AF:

0.00909

Gnomad4 NFE exome

AF:

0.00540

Gnomad4 OTH exome

AF:

0.00302

GnomAD4 genome

AF:

0.00336

AC:

512

AN:

152320

Hom.:

Cov.:

AF XY:

0.00358

AC XY:

267

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000986

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0130

Gnomad4 NFE

AF:

0.00478

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00370

Hom.:

Bravo

AF:

0.00262

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00509

AC:

ExAC

AF:

0.00465

AC:

562

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

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	Aug 23, 2017	p.Leu2984Phe in exon 38 of CHD7: This variant is not expected to have clinical s ignificance because it has been identified in 1.44% (73/5066) of Finnish chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs184814820). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 30, 2023	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CHD7: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 31, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CHARGE syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 05, 2016	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2019

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. -

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine 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

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.0081

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.80

T;T

MetaRNN

Benign

0.0047

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.1

L;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.54

N;N

REVEL

Benign

0.065

Sift

Benign

0.049

D;T

Sift4G

Benign

0.086

T;T

Polyphen

0.38

B;.

Vest4

0.27

MVP

0.69

MPC

0.68

ClinPred

0.019

GERP RS

4.5

Varity_R

0.049

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over