Variant 9-128683953-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001122821.2(SET):c.58C>A(p.Pro20Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SET
NM_001122821.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.13

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:

DYNC2I2 (HGNC:28296): (dynein 2 intermediate chain 2) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Defects in this gene are a cause of short-rib thoracic dysplasia 11 with or without polydactyly. [provided by RefSeq, Mar 2014]

DYNC2I2 links:

HMGA1P4 (HGNC:39093): (high mobility group AT-hook 1 pseudogene 4)

HMGA1P4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06116271).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
SET	NM_001122821.2 link	c.58C>A	p.Pro20Thr	missense_variant	Exon 1 of 8	NP_001116293.1	Q01105-1Q5VXV3
SET	NM_001374326.1 link	c.58C>A	p.Pro20Thr	missense_variant	Exon 2 of 9	NP_001361255.1
DYNC2I2	XM_047424057.1 link	c.-133+413G>T		intron_variant	Intron 1 of 9	XP_047280013.1
DYNC2I2	XM_011519179.3 link	c.-133+413G>T		intron_variant	Intron 1 of 9	XP_011517481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
SET	ENST00000372692.8 link	c.58C>A	p.Pro20Thr	missense_variant	Exon 1 of 8	1	ENSP00000361777.4	Q01105-1
SET	ENST00000686840.1 link	c.58C>A	p.Pro20Thr	missense_variant	Exon 2 of 9		ENSP00000509032.1	Q01105-1
SET	ENST00000686568.1 link	c.58C>A	p.Pro20Thr	missense_variant	Exon 1 of 7		ENSP00000508597.1	A0A8I5KS71

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1405390

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

693738

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 11, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.41

DANN

Benign

0.77

DEOGEN2

Benign

0.076

T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.60

T;T

M_CAP

Benign

0.0023

MetaRNN

Benign

0.061

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

.;L

PROVEAN

Pathogenic

-7.6

D;N

REVEL

Benign

0.091

Sift

Benign

0.24

T;T

Sift4G

Pathogenic

0.0

D;T

Polyphen

0.0

.;B

Vest4

0.12

MutPred

0.14

Gain of phosphorylation at P20 (P = 0.007);Gain of phosphorylation at P20 (P = 0.007);

MVP

0.39

MPC

1.8

ClinPred

0.083

GERP RS

-3.1

Varity_R

0.037

gMVP

0.40

Splicing

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