rs121434338

Positions:

• chr8-60822627-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_017780.4(CHD7):​c.3082A>G​(p.Ile1028Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.32

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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a domain Helicase ATP-binding (size 174) in uniprot entity CHD7_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_017780.4
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 8-60822627-A-G is Pathogenic according to our data. Variant chr8-60822627-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60822627-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD7	NM_017780.4	c.3082A>G	p.Ile1028Val	missense_variant	12/38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.3082A>G	p.Ile1028Val	missense_variant	12/38	5	NM_017780.4	ENSP00000392028	P1
CHD7	ENST00000524602.5	c.1717-39602A>G		intron_variant		1		ENSP00000437061
CHD7	ENST00000525508.1	c.3082A>G	p.Ile1028Val	missense_variant	11/12	5		ENSP00000436027
CHD7	ENST00000695853.1	c.3082A>G	p.Ile1028Val	missense_variant, NMD_transcript_variant	12/37			ENSP00000512218

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHARGE syndrome Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, University of Torino	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2022	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 2022). This missense change has been observed in individual(s) with CHARGE syndrome (PMID: 15300250, 16155193, 18073582, 20884005, 21158681, 22539353). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1028 of the CHD7 protein (p.Ile1028Val). Experimental studies have shown that this missense change affects CHD7 function (PMID: 25472840). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Apr 25, 2024	PS4, PS3, PM1, PM2, PP3- This variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 2022).In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. It is not present in population databases (gnomAD no frequency). It is reported previously as causative (PMID: 15300250, 16155193, 18073582, 20884005, 21158681, 22539353). Functional studies support pathogenic effect (PMID: 25472840). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2023	Published functional studies demonstrate a damaging effect; the I1028V variant causes a complete loss of function of CHD7 (Balasubramanian et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20884005, 16155193, 18073582, 25472840, 15300250, 22539353, 26563674, 22461308, 28475860, 21158681, 32914532, 34828433, 33189935) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 27, 2013	- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

May 31, 2022

ACMG categories: PS1,PS4,PM2,PM5 -

CHARGE syndrome;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	-0.040	N;N
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.92	N;N
REVEL	Pathogenic	0.78
Sift	Benign	0.048	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.75	P;P
Vest4		0.47
MutPred		0.86		Loss of catalytic residue at I1028 (P = 0.0656);Loss of catalytic residue at I1028 (P = 0.0656);
MVP		0.92
MPC		1.6
ClinPred		0.94	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.83		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434338; hg19: chr8-61735186;