12-53381734-A-C

Position:

• chr12-53381734-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138473.3(SP1):​c.83A>C​(p.Asn28Thr) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SP1 NM_138473.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.648

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

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=0.057748884).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SP1	NM_138473.3	c.83A>C	p.Asn28Thr	missense_variant	2/6	ENST00000327443.9	NP_612482.2
SP1	NM_003109.1	c.62A>C	p.Asn21Thr	missense_variant	2/6		NP_003100.1
SP1	NM_001251825.2	c.83A>C	p.Asn28Thr	missense_variant	2/6		NP_001238754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SP1	ENST00000327443.9	c.83A>C	p.Asn28Thr	missense_variant	2/6	1	NM_138473.3	ENSP00000329357.4
SP1	ENST00000426431.2	c.62A>C	p.Asn21Thr	missense_variant	2/6	1		ENSP00000404263.2
SP1	ENST00000548560.1	c.62A>C	p.Asn21Thr	missense_variant	1/2	2		ENSP00000458133.1
SP1	ENST00000551969.5	c.83A>C	p.Asn28Thr	missense_variant	2/3	3		ENSP00000457804.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

The c.83A>C (p.N28T) alteration is located in exon 2 (coding exon 2) of the SP1 gene. This alteration results from a A to C substitution at nucleotide position 83, causing the asparagine (N) at amino acid position 28 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.2
DANN	Benign	0.72
DEOGEN2	Benign	0.24	T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.65	T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.058	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	.;N;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.39	N;N;N;N
REVEL	Benign	0.051
Sift	Benign	0.038	D;D;D;D
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.37	.;B;.;.
Vest4		0.28, 0.33
MutPred		0.26		Gain of catalytic residue at N28 (P = 0);Gain of catalytic residue at N28 (P = 0);.;.;
MVP		0.45
MPC		0.16
ClinPred		0.084	T
GERP RS		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.061
gMVP		0.067

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

Publications

LitVar

Other links and lift over

dbSNP: rs374043734; hg19: chr12-53775518;