16-53156453-A-G

Variant names:

• chr16-53156453-A-G
• rs1407297584
• NM_001308319.2:c.364A>G

Variant summary

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

The NM_001308319.2(CHD9):​c.364A>G​(p.Ser122Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S122R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHD9 NM_001308319.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.48
• Publications: 0 publications found

Genes affected

CHD9 (HGNC:25701): (chromodomain helicase DNA binding protein 9) Predicted to enable ATP binding activity; ATP-dependent activity, acting on DNA; and DNA binding activity. Predicted to be involved in DNA duplex unwinding and chromatin organization. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.30715406).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308319.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD9	NM_001308319.2	MANE Select	c.364A>G	p.Ser122Gly	missense	Exon 2 of 39	NP_001295248.1	Q3L8U1-1
	CHD9	NM_001382353.1		c.364A>G	p.Ser122Gly	missense	Exon 2 of 39	NP_001369282.1	Q3L8U1-1
	CHD9	NM_001352127.3		c.364A>G	p.Ser122Gly	missense	Exon 2 of 39	NP_001339056.1	Q3L8U1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD9	ENST00000447540.6	TSL:5 MANE Select	c.364A>G	p.Ser122Gly	missense	Exon 2 of 39	ENSP00000396345.2	Q3L8U1-1
	CHD9	ENST00000398510.7	TSL:1	c.364A>G	p.Ser122Gly	missense	Exon 1 of 38	ENSP00000381522.3	Q3L8U1-1
	CHD9	ENST00000564845.5	TSL:1	c.364A>G	p.Ser122Gly	missense	Exon 2 of 39	ENSP00000455307.1	Q3L8U1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461676 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727114

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111856

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.047	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	1.1	L
PhyloP100		7.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.87	N
REVEL	Uncertain	0.43
Sift	Benign	0.34	T
Sift4G	Benign	0.45	T
Polyphen		0.037	B
Vest4		0.60
MutPred		0.18		Gain of catalytic residue at S122 (P = 0.0032)
MVP		0.65
MPC		0.36
ClinPred		0.65	D
GERP RS		5.7
PromoterAI		0.0034	Neutral
Varity_R		0.25
gMVP		0.60
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1407297584; hg19: chr16-53190365;