rs369792296

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001173467.3(SP7):c.1184G>A(p.Arg395His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,611,352 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R395C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 4 hom. )

Consequence

SP7
NM_001173467.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.421

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004576415).

BP6

Variant 12-53328258-C-T is Benign according to our data. Variant chr12-53328258-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1587263.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

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.1184G>A	p.Arg395His	missense	Exon 3 of 3	NP_001166938.1	Q8TDD2-1
SP7	NM_152860.2		c.1184G>A	p.Arg395His	missense	Exon 2 of 2	NP_690599.1	Q8TDD2-1
SP7	NM_001300837.2		c.1130G>A	p.Arg377His	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.1184G>A	p.Arg395His	missense	Exon 3 of 3	ENSP00000443827.2	Q8TDD2-1
SP7	ENST00000303846.3	TSL:1	c.1184G>A	p.Arg395His	missense	Exon 2 of 2	ENSP00000302812.3	Q8TDD2-1
SP7	ENST00000537210.2	TSL:1	c.1130G>A	p.Arg377His	missense	Exon 2 of 2	ENSP00000441367.2	Q8TDD2-2

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000542

AC:

132

AN:

243614

AF XY:

0.000747

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000274

Gnomad OTH exome

AF:

0.000508

GnomAD4 exome

AF:

0.000265

AC:

386

AN:

1459122

Hom.:

Cov.:

AF XY:

0.000402

AC XY:

292

AN XY:

725786

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44366

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25874

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.00418

AC:

359

AN:

85884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53130

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1110718

Other (OTH)

AF:

0.000183

AC:

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

111

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

AF:

0.000131

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41530

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00311

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000604

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.000256

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000612

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Osteogenesis imperfecta (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.83

M_CAP

Benign

0.0061

MetaRNN

Benign

0.0046

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

PhyloP100

0.42

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.35

REVEL

Benign

0.079

Sift

Benign

0.17

Sift4G

Benign

0.12

Polyphen

0.99

Vest4

0.21

MVP

0.20

MPC

0.56

ClinPred

0.023

GERP RS

2.6

Varity_R

0.043

Mutation Taster

=97/3

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over