16-58515795-C-T

Variant names:

• chr16-58515795-C-T
• rs1567373807
• NM_001160305.4:c.32C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001160305.4(SETD6):​c.32C>T​(p.Ala11Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000516 in 1,356,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000052 (0 hom.)
• Consequence: SETD6 NM_001160305.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.981

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17103013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD6	NM_001160305.4	c.32C>T	p.Ala11Val	missense_variant	Exon 2 of 8	ENST00000219315.9	NP_001153777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD6	ENST00000219315.9	c.32C>T	p.Ala11Val	missense_variant	Exon 2 of 8	1	NM_001160305.4	ENSP00000219315.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000332 AC: 4 AN: 120424 Hom.: 0 AF XY: 0.0000602 AC XY: 4 AN XY: 66476

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 SAS exome AF: 0.000123

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000371

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000516 AC: 7 AN: 1356944 Hom.: 0 Cov.: 32 AF XY: 0.00000746 AC XY: 5 AN XY: 669880

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000605

Gnomad4 SAS exome AF: 0.0000275

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000280

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.32C>T (p.A11V) alteration is located in exon 2 (coding exon 2) of the SETD6 gene. This alteration results from a C to T substitution at nucleotide position 32, causing the alanine (A) at amino acid position 11 to be replaced by a valine (V). 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	0.14
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	.;.;T;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.57	T;T;T;T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L;.;L;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.019
Sift	Benign	0.23	T;T;T;D
Sift4G	Benign	0.098	T;T;T;D
Polyphen		0.014	B;.;B;.
Vest4		0.16
MutPred		0.22		Loss of disorder (P = 0.0762);Loss of disorder (P = 0.0762);Loss of disorder (P = 0.0762);Loss of disorder (P = 0.0762);
MVP		0.26
MPC		0.24
ClinPred		0.22	T
GERP RS		-0.29
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.5
Varity_R		0.061
gMVP		0.13

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

Publications

LitVar

Other links and lift over

dbSNP: rs1567373807; hg19: chr16-58549699;