chr12-53382330-C-T

Variant names:

• chr12-53382330-C-T
• rs775596739
• NM_138473.3:c.383C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_138473.3(SP1):​c.383C>T​(p.Thr128Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SP1 NM_138473.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12
• Publications: 4 publications found

Genes affected

SP1 (HGNC:11205): (Sp1 transcription factor) The protein encoded by this gene is a zinc finger transcription factor that binds to GC-rich motifs of many promoters. The encoded protein is involved in many cellular processes, including cell differentiation, cell growth, apoptosis, immune responses, response to DNA damage, and chromatin remodeling. Post-translational modifications such as phosphorylation, acetylation, glycosylation, and proteolytic processing significantly affect the activity of this protein, which can be an activator or a repressor. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07389018).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138473.3. 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
	SP1	NM_138473.3	MANE Select	c.383C>T	p.Thr128Ile	missense	Exon 3 of 6	NP_612482.2
	SP1	NM_003109.1		c.362C>T	p.Thr121Ile	missense	Exon 3 of 6	NP_003100.1	P08047-2
	SP1	NM_001251825.2		c.239C>T	p.Thr80Ile	missense	Exon 3 of 6	NP_001238754.1	P08047-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SP1	ENST00000327443.9	TSL:1 MANE Select	c.383C>T	p.Thr128Ile	missense	Exon 3 of 6	ENSP00000329357.4	P08047-1
	SP1	ENST00000426431.2	TSL:1	c.362C>T	p.Thr121Ile	missense	Exon 3 of 6	ENSP00000404263.2	P08047-2
	SP1	ENST00000548560.1	TSL:2	c.362C>T	p.Thr121Ile	missense	Exon 2 of 2	ENSP00000458133.1	H3BVI2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.023
Sift	Benign	0.092	T
Sift4G	Benign	0.11	T
Polyphen		0.013	B
Vest4		0.29
MutPred		0.27		Gain of catalytic residue at T128 (P = 0.0047)
MVP		0.37
MPC		0.074
ClinPred		0.097	T
GERP RS		2.1
Varity_R		0.039
gMVP		0.31
Mutation Taster		=98/2	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: rs775596739; hg19: chr12-53776114; COSMIC: COSV105235658;