chr12-53382572-G-C

Position:

• chr12-53382572-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_138473.3(SP1):​c.625G>C​(p.Gly209Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SP1 NM_138473.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.76

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
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SP1	NM_138473.3	c.625G>C	p.Gly209Arg	missense_variant	3/6	ENST00000327443.9	NP_612482.2
SP1	NM_003109.1	c.604G>C	p.Gly202Arg	missense_variant	3/6		NP_003100.1
SP1	NM_001251825.2	c.481G>C	p.Gly161Arg	missense_variant	3/6		NP_001238754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SP1	ENST00000327443.9	c.625G>C	p.Gly209Arg	missense_variant	3/6	1	NM_138473.3	ENSP00000329357.4
SP1	ENST00000426431.2	c.604G>C	p.Gly202Arg	missense_variant	3/6	1		ENSP00000404263.2
SP1	ENST00000548560.1	c.604G>C	p.Gly202Arg	missense_variant	2/2	2		ENSP00000458133.1
SP1	ENST00000551969.5	c.481G>C	p.Gly161Arg	missense_variant	3/3	3		ENSP00000457804.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461864 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

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

Jul 25, 2023

The c.625G>C (p.G209R) alteration is located in exon 3 (coding exon 3) of the SP1 gene. This alteration results from a G to C substitution at nucleotide position 625, causing the glycine (G) at amino acid position 209 to be replaced by an arginine (R). 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	Pathogenic	0.82
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;D;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	.;M;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.3	D;D;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.94	.;P;.;.
Vest4		0.67, 0.67
MutPred		0.49		.;Gain of catalytic residue at P208 (P = 0.0019);.;.;
MVP		0.42
MPC		0.42
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.58

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: rs1938129791; hg19: chr12-53776356;