chr9-128683960-T-C

Position:

• chr9-128683960-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001122821.2(SET):​c.65T>C​(p.Leu22Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000444 in 1,557,540 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: SET NM_001122821.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0550

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]

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]

HMGA1P4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003423959).
• BP6: Variant 9-128683960-T-C is Benign according to our data. Variant chr9-128683960-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3025809.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 362 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SET	NM_001122821.2	c.65T>C	p.Leu22Pro	missense_variant	1/8		NP_001116293.1
SET	NM_001374326.1	c.65T>C	p.Leu22Pro	missense_variant	2/9		NP_001361255.1
DYNC2I2	XM_047424057.1	c.-133+406A>G		intron_variant			XP_047280013.1
DYNC2I2	XM_011519179.3	c.-133+406A>G		intron_variant			XP_011517481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SET	ENST00000372692.8	c.65T>C	p.Leu22Pro	missense_variant	1/8	1		ENSP00000361777.4
SET	ENST00000686840.1	c.65T>C	p.Leu22Pro	missense_variant	2/9			ENSP00000509032.1
SET	ENST00000686568.1	c.65T>C	p.Leu22Pro	missense_variant	1/7			ENSP00000508597.1

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 362 AN: 152140 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00840

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000556 AC: 91 AN: 163656 Hom.: 1 AF XY: 0.000505 AC XY: 44 AN XY: 87052

Gnomad AFR exome AF: 0.00908

Gnomad AMR exome AF: 0.000158

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000155

Gnomad OTH exome AF: 0.000217

GnomAD4 exome AF: 0.000235 AC: 330 AN: 1405282 Hom.: 2 Cov.: 30 AF XY: 0.000212 AC XY: 147 AN XY: 693684

Gnomad4 AFR exome AF: 0.00908

Gnomad4 AMR exome AF: 0.000110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000176

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000277

Gnomad4 OTH exome AF: 0.000343

GnomAD4 genome AF: 0.00238 AC: 362 AN: 152258 Hom.: 2 Cov.: 31 AF XY: 0.00236 AC XY: 176 AN XY: 74442

Gnomad4 AFR AF: 0.00838

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00246

ESP6500AA AF: 0.00837 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000508 AC: 57

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

SET: PP2, BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.3
DANN	Benign	0.36
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.43	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.26	.;N
PROVEAN	Pathogenic	-4.7	D;N
REVEL	Benign	0.025
Sift	Uncertain	0.014	D;T
Sift4G	Benign	0.089	T;T
Polyphen		0.0030	.;B
Vest4		0.084
MVP		0.068
MPC		2.6
ClinPred		0.025	T
GERP RS		1.3
Varity_R		0.080
gMVP		0.32

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs138894709; hg19: chr9-131446239;