12-53382840-C-T

Variant names:

• chr12-53382840-C-T
• rs183762099
• NM_138473.3:c.893C>T

Variant summary

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

The NM_138473.3(SP1):​c.893C>T​(p.Pro298Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P298R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SP1 NM_138473.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.77
• Publications: 5 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: 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=0.16660029).

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.893C>T	p.Pro298Leu	missense	Exon 3 of 6	NP_612482.2
	SP1	NM_003109.1		c.872C>T	p.Pro291Leu	missense	Exon 3 of 6	NP_003100.1	P08047-2
	SP1	NM_001251825.2		c.749C>T	p.Pro250Leu	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.893C>T	p.Pro298Leu	missense	Exon 3 of 6	ENSP00000329357.4	P08047-1
	SP1	ENST00000426431.2	TSL:1	c.872C>T	p.Pro291Leu	missense	Exon 3 of 6	ENSP00000404263.2	P08047-2
	SP1	ENST00000854917.1		c.271+622C>T		intron	N/A	ENSP00000524976.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251392 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

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: 53420

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.34	T
Eigen	Benign	0.088
Eigen_PC	Benign	0.068
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.64	N
PhyloP100		1.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.16
Sift	Benign	0.25	T
Sift4G	Benign	0.69	T
Polyphen		0.99	D
Vest4		0.28
MutPred		0.30		Gain of catalytic residue at T303 (P = 0.0015)
MVP		0.50
MPC		0.36
ClinPred		0.67	D
GERP RS		4.3
Varity_R		0.096
gMVP		0.23
Mutation Taster		=42/58	disease causing

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: rs183762099; hg19: chr12-53776624;