5-56911296-T-G

Variant names:

• chr5-56911296-T-G
• rs2257505
• NM_153706.4:c.226T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_153706.4(SETD9):​c.226T>G​(p.Ser76Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SETD9 NM_153706.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0610
• Publications: 49 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018361002).

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.226T>G	p.Ser76Ala	missense	Exon 2 of 6	NP_714917.2	Q8NE22-1
	SETD9	NM_001323018.2		c.148T>G	p.Ser50Ala	missense	Exon 2 of 6	NP_001309947.1
	SETD9	NM_001171990.3		c.226T>G	p.Ser76Ala	missense	Exon 2 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.226T>G	p.Ser76Ala	missense	Exon 2 of 6	ENSP00000285947.2	Q8NE22-1
	SETD9	ENST00000628593.1	TSL:1	c.226T>G	p.Ser76Ala	missense	Exon 2 of 6	ENSP00000486609.1	Q8NE22-2
	SETD9	ENST00000918990.1		c.226T>G	p.Ser76Ala	missense	Exon 2 of 6	ENSP00000589049.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000802 AC: 2 AN: 249246 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460300 Hom.: 0 Cov.: 50 AF XY: 0.00000413 AC XY: 3 AN XY: 726416

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.00 AC: 0 AN: 44416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000466 AC: 4 AN: 85924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111434

Other (OTH) AF: 0.00 AC: 0 AN: 60308

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.81
DEOGEN2	Benign	0.0077	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.044	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.6	N
PhyloP100		-0.061
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.026
Sift	Benign	0.43	T
Sift4G	Benign	0.91	T
Polyphen		0.0	B
Vest4		0.039
MutPred		0.23		Loss of disorder (P = 0.0449)
MVP		0.061
MPC		0.16
ClinPred		0.023	T
GERP RS		1.5
Varity_R		0.040
gMVP		0.098
Mutation Taster		=100/0	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: rs2257505; hg19: chr5-56207123;