NM_017780.4:c.5588C>A

Variant names:

• chr8-60851085-C-A
• rs753437069
• NM_017780.4:c.5588C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017780.4(CHD7):​c.5588C>A​(p.Pro1863Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1863L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.72
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• CHARGE syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Broad Center for Mendelian Genomics, ClinGen, G2P
• hypogonadotropic hypogonadism 5 with or without anosmia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33896434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD7	NM_017780.4	c.5588C>A	p.Pro1863Gln	missense_variant	Exon 27 of 38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.5588C>A	p.Pro1863Gln	missense_variant	Exon 27 of 38	5	NM_017780.4	ENSP00000392028.1
CHD7	ENST00000524602.5	c.1717-11144C>A		intron_variant	Intron 2 of 4	1		ENSP00000437061.1
CHD7	ENST00000527921.1	n.79C>A		non_coding_transcript_exon_variant	Exon 2 of 5	4
CHD7	ENST00000695853.1	n.5588C>A		non_coding_transcript_exon_variant	Exon 27 of 37			ENSP00000512218.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1419634 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 702008

African (AFR) AF: 0.00 AC: 0 AN: 32546

American (AMR) AF: 0.00 AC: 0 AN: 38430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25390

East Asian (EAS) AF: 0.00 AC: 0 AN: 37954

South Asian (SAS) AF: 0.00 AC: 0 AN: 80418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089124

Other (OTH) AF: 0.00 AC: 0 AN: 58976

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

CHARGE syndrome Uncertain:1

Dec 25, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CHD7-related disease. ClinVar contains an entry for this variant (Variation ID: 578946). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with glutamine at codon 1863 of the CHD7 protein (p.Pro1863Gln). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Benign	0.87
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.038
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.46
Sift	Benign	0.62	T
Sift4G	Benign	0.61	T
Polyphen		0.090	B
Vest4		0.51
MutPred		0.17		Gain of solvent accessibility (P = 0.0263);
MVP		0.66
MPC		1.6
ClinPred		0.84	D
GERP RS		5.3
Varity_R		0.11
gMVP		0.49
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs753437069; hg19: chr8-61763644;