5-56913933-C-G

Variant names:

• chr5-56913933-C-G
• rs754287203
• NM_153706.4:c.650C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_153706.4(SETD9):​c.650C>G​(p.Thr217Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T217M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SETD9 NM_153706.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.56
• Publications: 0 publications found

Genes affected

SETD9 (HGNC:28508): (SET domain containing 9) Predicted to enable lysine N-methyltransferase activity. Predicted to be involved in regulation of signal transduction by p53 class mediator. Predicted to be located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153706.4. 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
	SETD9	NM_153706.4	MANE Select	c.650C>G	p.Thr217Arg	missense	Exon 4 of 6	NP_714917.2	Q8NE22-1
	SETD9	NM_001323018.2		c.572C>G	p.Thr191Arg	missense	Exon 4 of 6	NP_001309947.1
	SETD9	NM_001171990.3		c.650C>G	p.Thr217Arg	missense	Exon 4 of 6	NP_001165461.1	Q8NE22-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD9	ENST00000285947.5	TSL:1 MANE Select	c.650C>G	p.Thr217Arg	missense	Exon 4 of 6	ENSP00000285947.2	Q8NE22-1
	SETD9	ENST00000628593.1	TSL:1	c.650C>G	p.Thr217Arg	missense	Exon 4 of 6	ENSP00000486609.1	Q8NE22-2
	SETD9	ENST00000918990.1		c.650C>G	p.Thr217Arg	missense	Exon 4 of 6	ENSP00000589049.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461710 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727178

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: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111878

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.6
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.19
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.023	D
Polyphen		0.99	D
Vest4		0.84
MutPred		0.29		Gain of helix (P = 0.0325)
MVP		0.61
MPC		0.82
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.40
gMVP		0.87
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs754287203; hg19: chr5-56209760;