dbSNP rs1554776500: SET:p.Trp82Gly (chr9-128691970-T-G) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_003011.4(SET):c.244T>G(p.Trp82Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 31)

Consequence

SET
NM_003011.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 7.35

Publications

0 publications found

Variant links:

Genes affected

SET (HGNC:10760): (SET nuclear proto-oncogene) The protein encoded by this gene inhibits acetylation of nucleosomes, especially histone H4, by histone acetylases (HAT). This inhibition is most likely accomplished by masking histone lysines from being acetylated, and the consequence is to silence HAT-dependent transcription. The encoded protein is part of a complex localized to the endoplasmic reticulum but is found in the nucleus and inhibits apoptosis following attack by cytotoxic T lymphocytes. This protein can also enhance DNA replication of the adenovirus genome. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

SET Gene-Disease associations (from GenCC):

intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
intellectual disability, autosomal dominant 58
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SET links:

ENSG00000305868 (HGNC:):

ENSG00000305868 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_003011.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 9-128691970-T-G is Pathogenic according to our data. Variant chr9-128691970-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 560206.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003011.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SET	NM_003011.4	MANE Select	c.244T>G	p.Trp82Gly	missense	Exon 3 of 8	NP_003002.2
SET	NM_001122821.2		c.283T>G	p.Trp95Gly	missense	Exon 3 of 8	NP_001116293.1
SET	NM_001374326.1		c.283T>G	p.Trp95Gly	missense	Exon 4 of 9	NP_001361255.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SET	ENST00000322030.13	TSL:1 MANE Select	c.244T>G	p.Trp82Gly	missense	Exon 3 of 8	ENSP00000318012.9
SET	ENST00000372692.8	TSL:1	c.283T>G	p.Trp95Gly	missense	Exon 3 of 8	ENSP00000361777.4
SET	ENST00000477806.5	TSL:1	n.435T>G		non_coding_transcript_exon	Exon 3 of 7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability, autosomal dominant 58 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

1.5

PhyloP100

7.3

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-11

REVEL

Pathogenic

0.81

Sift

Benign

0.072

Sift4G

Benign

0.15

Polyphen

0.17

Vest4

0.98

MutPred

0.96

Loss of stability (P = 0.0283)

MVP

0.95

MPC

2.6

ClinPred

0.98

GERP RS

5.0

Varity_R

0.94

gMVP

0.99

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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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