Genetic Variant SETD6:p.Glu42* (chr16-58515887-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001160305.4(SETD6):c.124G>T(p.Glu42*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000734 in 1,362,448 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. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

SETD6
NM_001160305.4 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0270

Publications

0 publications found

Variant links:

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

SETD6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SETD6	NM_001160305.4	MANE Select	c.124G>T	p.Glu42*	stop_gained	Exon 2 of 8	NP_001153777.1	Q8TBK2-1
SETD6	NM_024860.3		c.117+7G>T		splice_region intron	N/A	NP_079136.2	Q8TBK2-2
SETD6	NR_134583.1		n.176+7G>T		splice_region intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SETD6	ENST00000219315.9	TSL:1 MANE Select	c.124G>T	p.Glu42*	stop_gained	Exon 2 of 8	ENSP00000219315.5	Q8TBK2-1
SETD6	ENST00000427443.5	TSL:1	n.117+7G>T		splice_region intron	N/A	ENSP00000398033.1	E9PC53
SETD6	ENST00000898782.1		c.124G>T	p.Glu42*	stop_gained	Exon 2 of 7	ENSP00000568841.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.34e-7

AC:

AN:

1362448

Hom.:

Cov.:

AF XY:

0.00000149

AC XY:

AN XY:

673034

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27832

American (AMR)

AF:

0.00

AC:

AN:

32088

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23316

East Asian (EAS)

AF:

0.00

AC:

AN:

32546

South Asian (SAS)

AF:

0.00

AC:

AN:

75610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36430

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5378

European-Non Finnish (NFE)

AF:

9.32e-7

AC:

AN:

1072410

Other (OTH)

AF:

0.00

AC:

AN:

56838

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.17

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.078

PhyloP100

0.027

Vest4

0.023

GERP RS

4.2

PromoterAI

0.0064

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over