chr12-53328258-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

2
17

Clinical Significance

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

Conservation

PhyloP100: 0.421
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 1587263.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS2
High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SP7NM_001173467.3 linkuse as main transcriptc.1184G>A p.Arg395His missense_variant 3/3 ENST00000536324.4
SP7NM_152860.2 linkuse as main transcriptc.1184G>A p.Arg395His missense_variant 2/2
SP7NM_001300837.2 linkuse as main transcriptc.1130G>A p.Arg377His missense_variant 3/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SP7ENST00000536324.4 linkuse as main transcriptc.1184G>A p.Arg395His missense_variant 3/32 NM_001173467.3 P1Q8TDD2-1
SP7ENST00000303846.3 linkuse as main transcriptc.1184G>A p.Arg395His missense_variant 2/21 P1Q8TDD2-1
SP7ENST00000537210.2 linkuse as main transcriptc.1130G>A p.Arg377His missense_variant 2/21 Q8TDD2-2

Frequencies

GnomAD3 genomes
AF:
0.000131
AC:
20
AN:
152112
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.000542
AC:
132
AN:
243614
Hom.:
0
AF XY:
0.000747
AC XY:
99
AN XY:
132472
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 SAS exome
AF:
0.00412
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.:
4
Cov.:
29
AF XY:
0.000402
AC XY:
292
AN XY:
725786
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00418
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.000183
GnomAD4 genome
AF:
0.000131
AC:
20
AN:
152230
Hom.:
0
Cov.:
32
AF XY:
0.000188
AC XY:
14
AN XY:
74428
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00311
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000550
Hom.:
0
Bravo
AF:
0.0000416
ESP6500AA
AF:
0.000256
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000612
AC:
74
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Osteogenesis imperfecta Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenApr 01, 2019- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 12, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.24
T;T;.
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.31
FATHMM_MKL
Benign
0.45
N
LIST_S2
Benign
0.83
.;T;T
M_CAP
Benign
0.0061
T
MetaRNN
Benign
0.0046
T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.0
N;N;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
0.35
N;N;N
REVEL
Benign
0.079
Sift
Benign
0.17
T;T;T
Sift4G
Benign
0.12
T;T;T
Polyphen
0.99
D;D;.
Vest4
0.21
MVP
0.20
MPC
0.56
ClinPred
0.023
T
GERP RS
2.6
Varity_R
0.043

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.

Other links and lift over

dbSNP: rs369792296; hg19: chr12-53722042; COSMIC: COSV100382143; COSMIC: COSV100382143; API