Genetic Variant SP1:p.Ile171Thr (chr12-53382459-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_138473.3(SP1):c.512T>C(p.Ile171Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,884 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: 0.0000041 ( 0 hom. )

Consequence

SP1
NM_138473.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.98

Variant links:

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]

SP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SP1	NM_138473.3 link	c.512T>C	p.Ile171Thr	missense_variant	Exon 3 of 6	ENST00000327443.9	NP_612482.2	P08047-1
SP1	NM_003109.1 link	c.491T>C	p.Ile164Thr	missense_variant	Exon 3 of 6		NP_003100.1	P08047-2
SP1	NM_001251825.2 link	c.368T>C	p.Ile123Thr	missense_variant	Exon 3 of 6		NP_001238754.1	P08047-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SP1	ENST00000327443.9 link	c.512T>C	p.Ile171Thr	missense_variant	Exon 3 of 6	1	NM_138473.3	ENSP00000329357.4	P08047-1
SP1	ENST00000426431.2 link	c.491T>C	p.Ile164Thr	missense_variant	Exon 3 of 6	1		ENSP00000404263.2	P08047-2
SP1	ENST00000548560.1 link	c.491T>C	p.Ile164Thr	missense_variant	Exon 2 of 2	2		ENSP00000458133.1	H3BVI2
SP1	ENST00000551969.5 link	c.368T>C	p.Ile123Thr	missense_variant	Exon 3 of 3	3		ENSP00000457804.1	H3BUU5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251288

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135886

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.512T>C (p.I171T) alteration is located in exon 3 (coding exon 3) of the SP1 gene. This alteration results from a T to C substitution at nucleotide position 512, causing the isoleucine (I) at amino acid position 171 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

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;D;.;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.70

D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

.;M;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.8

D;N;N;D

REVEL

Uncertain

0.38

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D

Polyphen

0.95

.;P;.;.

Vest4

0.92, 0.93

MutPred

0.67

.;Gain of catalytic residue at V167 (P = 5e-04);.;.;

MVP

0.72

MPC

0.23

ClinPred

0.98

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.32

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over