rs761409446

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS1

The NM_017780.4(CHD7):c.8213C>T(p.Thr2738Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000323 in 1,611,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T2738T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

CHD7
NM_017780.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 5.55

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 8-60865152-C-T is Benign according to our data. Variant chr8-60865152-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 363481.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000322 (47/1459612) while in subpopulation NFE AF = 0.0000423 (47/1111096). AF 95% confidence interval is 0.0000326. There are 0 homozygotes in GnomAdExome4. There are 28 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD7	NM_017780.4 link	c.8213C>T	p.Thr2738Met	missense_variant	Exon 38 of 38	ENST00000423902.7	NP_060250.2	Q9P2D1-1Q6ZWF9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7 link	c.8213C>T	p.Thr2738Met	missense_variant	Exon 38 of 38	5	NM_017780.4	ENSP00000392028.1		Q9P2D1-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000164

AC:

AN:

244480

AF XY:

0.0000151

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000361

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1459612

Hom.:

Cov.:

AF XY:

0.0000386

AC XY:

AN XY:

725874

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44444

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26044

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

85750

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000423

AC:

AN:

1111096

Other (OTH)

AF:

0.00

AC:

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41478

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000659

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 05, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypogonadotropic hypogonadism 5 with or without anosmia

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

CHARGE syndrome

Benign:1

Oct 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Aug 10, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.63

MetaRNN

Uncertain

0.67

D;D

MetaSVM

Uncertain

-0.024

MutationAssessor

Benign

1.8

L;.

PhyloP100

5.5

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.20

Sift

Uncertain

0.012

D;D

Sift4G

Uncertain

0.018

D;D

Polyphen

1.0

D;.

Vest4

0.56

MVP

0.79

MPC

0.65

ClinPred

0.74

GERP RS

5.6

Varity_R

0.080

gMVP

0.48

Mutation Taster

=49/51

disease causing

(source)

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

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rs761409446

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over