Genetic Variant NM_001173467.3:c.1253C>A (chr12-53328189-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001173467.3(SP7):c.1253C>A(p.Ala418Asp) 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 1,460,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SP7
NM_001173467.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.850

Variant links:

Genes affected

SP7 (HGNC:17321): (Sp7 transcription factor) This gene encodes a member of the Sp subfamily of Sp/XKLF transcription factors. Sp family proteins are sequence-specific DNA-binding proteins characterized by an amino-terminal trans-activation domain and three carboxy-terminal zinc finger motifs. This protein is a bone specific transcription factor and is required for osteoblast differentiation and bone formation.[provided by RefSeq, Jul 2010]

SP7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08779439).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SP7	NM_001173467.3 link	c.1253C>A	p.Ala418Asp	missense_variant	Exon 3 of 3	ENST00000536324.4	NP_001166938.1	Q8TDD2-1
SP7	NM_152860.2 link	c.1253C>A	p.Ala418Asp	missense_variant	Exon 2 of 2		NP_690599.1	Q8TDD2-1
SP7	NM_001300837.2 link	c.1199C>A	p.Ala400Asp	missense_variant	Exon 3 of 3		NP_001287766.1	Q8TDD2-2A0A024RAY8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SP7	ENST00000536324.4 link	c.1253C>A	p.Ala418Asp	missense_variant	Exon 3 of 3	2	NM_001173467.3	ENSP00000443827.2	Q8TDD2-1
SP7	ENST00000303846.3 link	c.1253C>A	p.Ala418Asp	missense_variant	Exon 2 of 2	1		ENSP00000302812.3	Q8TDD2-1
SP7	ENST00000537210.2 link	c.1199C>A	p.Ala400Asp	missense_variant	Exon 2 of 2	1		ENSP00000441367.2	Q8TDD2-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000408

AC:

AN:

245212

Hom.:

AF XY:

0.00000748

AC XY:

AN XY:

133628

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460838

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726694

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1253C>A (p.A418D) alteration is located in exon 3 (coding exon 2) of the SP7 gene. This alteration results from a C to A substitution at nucleotide position 1253, causing the alanine (A) at amino acid position 418 to be replaced by an aspartic acid (D). 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

0.14

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.32

T;T;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.69

.;T;T

M_CAP

Benign

0.0023

MetaRNN

Benign

0.088

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

N;N;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.43

N;N;N

REVEL

Benign

0.11

Sift

Uncertain

0.010

D;D;D

Sift4G

Benign

0.37

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.54

MVP

0.043

MPC

0.56

ClinPred

0.092

GERP RS

0.055

Varity_R

0.35

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