Variant 9-128691964-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The NM_003011.4(SET):c.238A>T(p.Asn80Tyr) 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

SET
NM_003011.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.57

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a helix (size 50) in uniprot entity SET_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003011.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SET. . Gene score misZ 2.6574 (greater than the threshold 3.09). Trascript score misZ 3.2041 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant non-syndromic intellectual disability, intellectual disability, autosomal dominant 58.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SET	NM_003011.4 linkuse as main transcript	c.238A>T	p.Asn80Tyr	missense_variant	3/8	ENST00000322030.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SET	ENST00000322030.13 linkuse as main transcript	c.238A>T	p.Asn80Tyr	missense_variant	3/8	1	NM_003011.4	P1	Q01105-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 58

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Nov 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;.;.;.;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.72

T;T;T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.91

D;D;D;D;D

MetaSVM

Benign

-0.41

MutationAssessor

Pathogenic

2.9

M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.3

D;D;D;D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0030

D;D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D;D

Polyphen

0.98

D;.;P;.;.

Vest4

0.82

MutPred

0.70

Loss of MoRF binding (P = 0.0975);.;.;.;.;

MVP

0.68

MPC

3.2

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over