rs750214154

Positions:

• chr8-60823985-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_017780.4(CHD7):​c.3347A>G​(p.Lys1116Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.95

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 Likely_pathogenic. Variant got 6 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: MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD7	NM_017780.4	c.3347A>G	p.Lys1116Arg	missense_variant	13/38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.3347A>G	p.Lys1116Arg	missense_variant	13/38	5	NM_017780.4	ENSP00000392028	P1
CHD7	ENST00000524602.5	c.1717-38244A>G		intron_variant		1		ENSP00000437061
CHD7	ENST00000525508.1	c.3347A>G	p.Lys1116Arg	missense_variant	12/12	5		ENSP00000436027
CHD7	ENST00000695853.1	c.3347A>G	p.Lys1116Arg	missense_variant, NMD_transcript_variant	13/37			ENSP00000512218

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248874 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134996

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461416 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726936

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHARGE syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a VUS - 3A. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from lysine to arginine (exon 13). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is a ubiquitinated lysine in the SNF2 family N-terminal domain (PDB) (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0804 - Variant has previously been described as variant of uncertain significance (ClinVar) (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1203 - Variant shown to be de novo in proband (parental status confirmed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 18, 2022	This variant is present in population databases (rs750214154, gnomAD 0.0009%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CHD7 protein function. ClinVar contains an entry for this variant (Variation ID: 529137). This variant has not been reported in the literature in individuals affected with CHD7-related conditions. This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1116 of the CHD7 protein (p.Lys1116Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.81
Sift	Benign	0.048	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.71
MutPred		0.56		Gain of MoRF binding (P = 0.0685);Gain of MoRF binding (P = 0.0685);
MVP		0.94
MPC		1.6
ClinPred		0.94	D
GERP RS		5.7
Varity_R		0.60
gMVP		0.74

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: rs750214154; hg19: chr8-61736544;