12-53328344-G-A

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.1098C>T(p.Ser366=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.97 in 1,612,252 control chromosomes in the GnomAD database, including 760,994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (63966 hom., cov: 33)
  • Exomes 𝑓: 0.98 (697028 hom.)
• Consequence: SP7 NM_001173467.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0480

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=-0.65).
• BP6: Variant 12-53328344-G-A is Benign according to our data. Variant chr12-53328344-G-A is described in ClinVar as [Benign]. Clinvar id is 285778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-53328344-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.048 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SP7	NM_001173467.3	c.1098C>T	p.Ser366=	synonymous_variant	3/3	ENST00000536324.4
SP7	NM_152860.2	c.1098C>T	p.Ser366=	synonymous_variant	2/2
SP7	NM_001300837.2	c.1044C>T	p.Ser348=	synonymous_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SP7	ENST00000536324.4	c.1098C>T	p.Ser366=	synonymous_variant	3/3	2	NM_001173467.3	P1
SP7	ENST00000303846.3	c.1098C>T	p.Ser366=	synonymous_variant	2/2	1		P1
SP7	ENST00000537210.2	c.1044C>T	p.Ser348=	synonymous_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.909 AC: 138278 AN: 152128 Hom.: 63936 Cov.: 33

Gnomad AFR AF: 0.720

Gnomad AMI AF: 0.987

Gnomad AMR AF: 0.961

Gnomad ASJ AF: 0.991

Gnomad EAS AF: 0.959

Gnomad SAS AF: 0.948

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.985

Gnomad OTH AF: 0.944

GnomAD3 exomes AF: 0.963 AC: 239096 AN: 248226 Hom.: 115704 AF XY: 0.966 AC XY: 130102 AN XY: 134668

Gnomad AFR exome AF: 0.711

Gnomad AMR exome AF: 0.982

Gnomad ASJ exome AF: 0.990

Gnomad EAS exome AF: 0.962

Gnomad SAS exome AF: 0.952

Gnomad FIN exome AF: 0.999

Gnomad NFE exome AF: 0.986

Gnomad OTH exome AF: 0.976

GnomAD4 exome AF: 0.976 AC: 1425092 AN: 1460006 Hom.: 697028 Cov.: 65 AF XY: 0.976 AC XY: 708826 AN XY: 725996

Gnomad4 AFR exome AF: 0.695

Gnomad4 AMR exome AF: 0.978

Gnomad4 ASJ exome AF: 0.990

Gnomad4 EAS exome AF: 0.978

Gnomad4 SAS exome AF: 0.952

Gnomad4 FIN exome AF: 0.998

Gnomad4 NFE exome AF: 0.986

Gnomad4 OTH exome AF: 0.964

GnomAD4 genome AF: 0.909 AC: 138363 AN: 152246 Hom.: 63966 Cov.: 33 AF XY: 0.911 AC XY: 67819 AN XY: 74442

Gnomad4 AFR AF: 0.719

Gnomad4 AMR AF: 0.961

Gnomad4 ASJ AF: 0.991

Gnomad4 EAS AF: 0.959

Gnomad4 SAS AF: 0.949

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.985

Gnomad4 OTH AF: 0.945

Alfa AF: 0.954 Hom.: 47023

Bravo AF: 0.897

Asia WGS AF: 0.935 AC: 3252 AN: 3478

EpiCase AF: 0.981

EpiControl AF: 0.981

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type 12 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	- -

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:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	0.61
Dann	Benign	0.88

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: rs7139272; hg19: chr12-53722128; COSMIC: COSV58191462; COSMIC: COSV58191462;