12-53328314-A-G

Position:

• chr12-53328314-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001173467.3(SP7):​c.1128T>C​(p.His376=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.992 in 1,611,130 control chromosomes in the GnomAD database, including 792,947 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70117 hom., cov: 33)
  • Exomes 𝑓: 1.0 (722830 hom.)
• Consequence: SP7 NM_001173467.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.955

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 12-53328314-A-G is Benign according to our data. Variant chr12-53328314-A-G is described in ClinVar as [Benign]. Clinvar id is 285779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-53328314-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.955 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SP7	NM_001173467.3	c.1128T>C	p.His376=	synonymous_variant	3/3	ENST00000536324.4
SP7	NM_152860.2	c.1128T>C	p.His376=	synonymous_variant	2/2
SP7	NM_001300837.2	c.1074T>C	p.His358=	synonymous_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SP7	ENST00000536324.4	c.1128T>C	p.His376=	synonymous_variant	3/3	2	NM_001173467.3	P1
SP7	ENST00000303846.3	c.1128T>C	p.His376=	synonymous_variant	2/2	1		P1
SP7	ENST00000537210.2	c.1074T>C	p.His358=	synonymous_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.958 AC: 145668 AN: 152114 Hom.: 70068 Cov.: 33

Gnomad AFR AF: 0.853

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.983

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.991

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.974

GnomAD3 exomes AF: 0.989 AC: 243542 AN: 246302 Hom.: 120587 AF XY: 0.992 AC XY: 132526 AN XY: 133630

Gnomad AFR exome AF: 0.845

Gnomad AMR exome AF: 0.993

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.995

GnomAD4 exome AF: 0.995 AC: 1451771 AN: 1458898 Hom.: 722830 Cov.: 74 AF XY: 0.996 AC XY: 722489 AN XY: 725512

Gnomad4 AFR exome AF: 0.835

Gnomad4 AMR exome AF: 0.991

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.990

GnomAD4 genome AF: 0.958 AC: 145777 AN: 152232 Hom.: 70117 Cov.: 33 AF XY: 0.959 AC XY: 71359 AN XY: 74442

Gnomad4 AFR AF: 0.853

Gnomad4 AMR AF: 0.983

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.974

Alfa AF: 0.978 Hom.: 36660

Bravo AF: 0.951

Asia WGS AF: 0.994 AC: 3458 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type 12 Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.21
DANN	Benign	0.45

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: rs7138938; hg19: chr12-53722098; COSMIC: COSV58191456; COSMIC: COSV58191456;