Genetic Variant SP7:p.Ala418Asp (chr12-53328189-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A418V) has been classified 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

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

osteogenesis imperfecta type 12
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
osteogenesis imperfecta type 4
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SP7 links:

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ACMG classification

Classification was made for transcript

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=0.08779439).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001173467.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SP7	NM_001173467.3	MANE Select	c.1253C>A	p.Ala418Asp	missense	Exon 3 of 3	NP_001166938.1	Q8TDD2-1
SP7	NM_152860.2		c.1253C>A	p.Ala418Asp	missense	Exon 2 of 2	NP_690599.1	Q8TDD2-1
SP7	NM_001300837.2		c.1199C>A	p.Ala400Asp	missense	Exon 3 of 3	NP_001287766.1	Q8TDD2-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SP7	ENST00000536324.4	TSL:2 MANE Select	c.1253C>A	p.Ala418Asp	missense	Exon 3 of 3	ENSP00000443827.2	Q8TDD2-1
SP7	ENST00000303846.3	TSL:1	c.1253C>A	p.Ala418Asp	missense	Exon 2 of 2	ENSP00000302812.3	Q8TDD2-1
SP7	ENST00000537210.2	TSL:1	c.1199C>A	p.Ala400Asp	missense	Exon 2 of 2	ENSP00000441367.2	Q8TDD2-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000408

AC:

AN:

245212

AF XY:

0.00000748

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 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

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.0000224

AC:

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111652

Other (OTH)

AF:

0.00

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.32

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.69

M_CAP

Benign

0.0023

MetaRNN

Benign

0.088

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

PhyloP100

0.85

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.43

REVEL

Benign

0.11

Sift

Uncertain

0.010

Sift4G

Benign

0.37

Polyphen

0.0

Vest4

0.54

MVP

0.043

MPC

0.56

ClinPred

0.092

GERP RS

0.055

Varity_R

0.35

Mutation Taster

=75/25

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over