NM_003011.4:c.73+342G>C

Variant names:

• chr9-128689997-G-C
• rs1423640750
• NM_003011.4:c.73+342G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003011.4(SET):​c.73+342G>C variant causes a intron 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SET NM_003011.4 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.891
• Publications: 0 publications found

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, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17901072).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SET	NM_003011.4	MANE Select	c.73+342G>C		intron	N/A	NP_003002.2	Q01105-2
	SET	NM_001248001.2		c.11G>C	p.Arg4Pro	missense	Exon 1 of 8	NP_001234930.1	A0A8J8YYJ1
	SET	NM_001122821.2		c.113-1173G>C		intron	N/A	NP_001116293.1	Q5VXV3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SET	ENST00000322030.13	TSL:1 MANE Select	c.73+342G>C		intron	N/A	ENSP00000318012.9	Q01105-2
	SET	ENST00000372692.8	TSL:1	c.113-1173G>C		intron	N/A	ENSP00000361777.4	Q01105-1
	SET	ENST00000372686.6	TSL:2	c.11G>C	p.Arg4Pro	missense	Exon 1 of 8	ENSP00000361771.6	A0A8J8YYJ1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 894388 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 425230

African (AFR) AF: 0.00 AC: 0 AN: 16876

American (AMR) AF: 0.00 AC: 0 AN: 7318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9178

East Asian (EAS) AF: 0.00 AC: 0 AN: 4676

South Asian (SAS) AF: 0.00 AC: 0 AN: 29366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2078

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 791276

Other (OTH) AF: 0.00 AC: 0 AN: 29966

GnomAD4 genome Cov.: 28

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.89
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.039
Sift	Uncertain	0.011	D
Sift4G	Benign	0.18	T
Vest4		0.24
MutPred		0.25		Gain of glycosylation at R4 (P = 0.007)
MVP		0.20
ClinPred		0.52	D
GERP RS		0.43
PromoterAI		0.059	Neutral
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs1423640750; hg19: chr9-131452276;