16-58516007-A-G

Position:

• chr16-58516007-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001160305.4(SETD6):​c.244A>G​(p.Ser82Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000862 in 1,391,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000086 (0 hom.)
• Consequence: SETD6 NM_001160305.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.82

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28929138).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETD6	NM_001160305.4	c.244A>G	p.Ser82Gly	missense_variant	2/8	ENST00000219315.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETD6	ENST00000219315.9	c.244A>G	p.Ser82Gly	missense_variant	2/8	1	NM_001160305.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000862 AC: 12 AN: 1391544 Hom.: 0 Cov.: 32 AF XY: 0.00000870 AC XY: 6 AN XY: 689628

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000101

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2023

The c.244A>G (p.S82G) alteration is located in exon 2 (coding exon 2) of the SETD6 gene. This alteration results from a A to G substitution at nucleotide position 244, causing the serine (S) at amino acid position 82 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.033	.;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.040
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.61	T;T;T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.34	.;.;N
MutationTaster	Benign	0.96	N;N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.048	D;D;T
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.018	B;.;B
Vest4		0.090
MutPred		0.58		.;.;Loss of phosphorylation at S82 (P = 0.0777);
MVP		0.47
MPC		0.26
ClinPred		0.56	D
GERP RS		3.0
Varity_R		0.26
gMVP		0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs1271673885; hg19: chr16-58549911;