12-53328349-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001173467.3(SP7):c.1093C>T(p.Arg365Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,460,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.97

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001173467.3 Downstream stopcodon found after 14 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SP7	NM_001173467.3	c.1093C>T	p.Arg365Ter	stop_gained	3/3	ENST00000536324.4
SP7	NM_152860.2	c.1093C>T	p.Arg365Ter	stop_gained	2/2
SP7	NM_001300837.2	c.1039C>T	p.Arg347Ter	stop_gained	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SP7	ENST00000536324.4	c.1093C>T	p.Arg365Ter	stop_gained	3/3	2	NM_001173467.3	P1
SP7	ENST00000303846.3	c.1093C>T	p.Arg365Ter	stop_gained	2/2	1		P1
SP7	ENST00000537210.2	c.1039C>T	p.Arg347Ter	stop_gained	2/2	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248306 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134708

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: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460182 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 726208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type 12 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Jun 25, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Breda Genetics srl	Dec 19, 2020	The variant c.1093C>T (p.Arg365*) in the SP7 gene is reported as uncertain for osteogenesis imperfecta type 12 in ClinVar (Variation ID: 829874) and as probably not affecting function in Global Variome shared LOVD database v.3.0. It creates a premature stop codon at amino acid position Arg365, which is likely to result in a truncated protein. However, the variant falls in the last exon of the gene and 67 amino acid position upstream the wild-type stop codon, therefore it is uncertain if the alteration of the C-terminal end of the SP7 protein can be considered as pathogenic for the disease. The variant is reported with an estimated allele frequency of 0.000004027 in gnomAD exomes, with no homozygous individuals reported. Based on ACMG variant interpretation guidelines we classify this variant as uncertain; however we cannot exclude that it is a rare benign variant. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 24, 2021

This sequence change creates a premature translational stop signal (p.Arg365*) in the SP7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 67 amino acid(s) of the SP7 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SP7-related conditions. ClinVar contains an entry for this variant (Variation ID: 829874). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.95
GERP RS		-0.054

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

Other links and lift over

dbSNP: rs1427780619; hg19: chr12-53722133; COSMIC: COSV100382078; COSMIC: COSV100382078;