NM_017780.4:c.986A>G

Variant names:

• chr8-60742418-A-G
• rs777040556
• NM_017780.4:c.986A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_017780.4(CHD7):​c.986A>G​(p.Asn329Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.90
• Publications: 1 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.121445686).
• BP6: Variant 8-60742418-A-G is Benign according to our data. Variant chr8-60742418-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 267415.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD7	NM_017780.4	c.986A>G	p.Asn329Ser	missense_variant	Exon 2 of 38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.986A>G	p.Asn329Ser	missense_variant	Exon 2 of 38	5	NM_017780.4	ENSP00000392028.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000802 AC: 2 AN: 249296 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461660 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727114

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111822

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

CHARGE syndrome Uncertain:1 Benign:1

Jun 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.073	T;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.016
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.46	N;N;N
PhyloP100		5.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.040	N;N;N
REVEL	Benign	0.078
Sift	Benign	0.46	T;T;T
Sift4G	Benign	0.84	T;T;T
Polyphen		0.024	B;.;.
Vest4		0.71
MutPred		0.25		Gain of catalytic residue at N329 (P = 0.0811);Gain of catalytic residue at N329 (P = 0.0811);Gain of catalytic residue at N329 (P = 0.0811);
MVP		0.69
MPC		0.16
ClinPred		0.27	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.068
gMVP		0.25
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs777040556; hg19: chr8-61654977;