Genetic Variant NM_001366418.1:c.2824G>C (chr1-150960883-G-C) – 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_001366418.1(SETDB1):c.2824G>C(p.Glu942Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,208 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SETDB1
NM_001366418.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.35

Publications

0 publications found

Variant links:

Genes affected

SETDB1 (HGNC:10761): (SET domain bifurcated histone lysine methyltransferase 1) This gene encodes a histone methyltransferase which regulates histone methylation, gene silencing, and transcriptional repression. This gene has been identified as a target for treatment in Huntington Disease, given that gene silencing and transcription dysfunction likely play a role in the disease pathogenesis. Alternatively spliced transcript variants of this gene have been described.[provided by RefSeq, Jun 2011]

SETDB1 links:

CERS2 (HGNC:14076): (ceramide synthase 2) This gene encodes a protein that has sequence similarity to yeast longevity assurance gene 1. Mutation or overexpression of the related gene in yeast has been shown to alter yeast lifespan. The human protein may play a role in the regulation of cell growth. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jul 2008]

CERS2 links:

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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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETDB1	NM_001366418.1 link	c.2824G>C	p.Glu942Gln	missense_variant	Exon 16 of 22	ENST00000692827.1	NP_001353347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETDB1	ENST00000692827.1 link	c.2824G>C	p.Glu942Gln	missense_variant	Exon 16 of 22		NM_001366418.1	ENSP00000509425.1		A0A8I5KT93

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459208

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725786

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.00

AC:

AN:

44558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25800

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

85888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110500

Other (OTH)

AF:

0.0000166

AC:

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 22, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2821G>C (p.E941Q) alteration is located in exon 16 (coding exon 15) of the SETDB1 gene. This alteration results from a G to C substitution at nucleotide position 2821, causing the glutamic acid (E) at amino acid position 941 to be replaced by a glutamine (Q). 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

0.20

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.61

D;D;D

MetaSVM

Uncertain

0.34

MutationAssessor

Uncertain

2.1

M;M;.

PhyloP100

7.3

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.83

N;N;N

REVEL

Uncertain

0.34

Sift

Uncertain

0.027

D;D;D

Sift4G

Uncertain

0.040

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.40

MutPred

0.29

Gain of MoRF binding (P = 0.0448);Gain of MoRF binding (P = 0.0448);Gain of MoRF binding (P = 0.0448);

MVP

0.80

MPC

1.6

ClinPred

0.87

GERP RS

5.0

Varity_R

0.23

gMVP

0.29

Mutation Taster

=86/14

polymorphism

(source)

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

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NM_001366418.1:c.2824G>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over