chr16-58515887-G-A

Variant names:

• chr16-58515887-G-A
• rs1353872820
• NM_001160305.4:c.124G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001160305.4(SETD6):​c.124G>A​(p.Glu42Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000954 in 1,362,448 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000095 (0 hom.)
• Consequence: SETD6 NM_001160305.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0270
• Publications: 0 publications found

Genes affected

SETD6 (HGNC:26116): (SET domain containing 6, protein lysine methyltransferase) This gene encodes a methyltransferase that adds a methyl group to the histone H2AZ, which is involved in nuclear receptor-dependent transcription. The protein also interacts with several endogenous proteins which are involved in nuclear hormone receptor signaling. A related pseudogene is located on chromosome 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

SETD6 Gene-Disease associations (from GenCC):

• colorectal cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06063652).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001160305.4. 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
	SETD6	NM_001160305.4	MANE Select	c.124G>A	p.Glu42Lys	missense	Exon 2 of 8	NP_001153777.1	Q8TBK2-1
	SETD6	NM_024860.3		c.117+7G>A		splice_region intron	N/A	NP_079136.2	Q8TBK2-2
	SETD6	NR_134583.1		n.176+7G>A		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD6	ENST00000219315.9	TSL:1 MANE Select	c.124G>A	p.Glu42Lys	missense	Exon 2 of 8	ENSP00000219315.5	Q8TBK2-1
	SETD6	ENST00000427443.5	TSL:1	n.117+7G>A		splice_region intron	N/A	ENSP00000398033.1	E9PC53
	SETD6	ENST00000898782.1		c.124G>A	p.Glu42Lys	missense	Exon 2 of 7	ENSP00000568841.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000182 AC: 2 AN: 110154 AF XY: 0.0000323

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000281

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000954 AC: 13 AN: 1362448 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 9 AN XY: 673034

African (AFR) AF: 0.00 AC: 0 AN: 27832

American (AMR) AF: 0.00 AC: 0 AN: 32088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23316

East Asian (EAS) AF: 0.000246 AC: 8 AN: 32546

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 75610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5378

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1072410

Other (OTH) AF: 0.0000352 AC: 2 AN: 56838

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.1
DANN	Benign	0.85
DEOGEN2	Benign	0.0099	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.027
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.11
Sift	Benign	0.72	T
Sift4G	Benign	0.84	T
Polyphen		0.72	P
Vest4		0.093
MutPred		0.37		Gain of catalytic residue at E42 (P = 0.0094)
MVP		0.16
MPC		0.21
ClinPred		0.14	T
GERP RS		4.2
PromoterAI		0.018	Neutral
Varity_R		0.13
gMVP		0.36
Mutation Taster		=95/5	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: rs1353872820; hg19: chr16-58549791;