rs777225684

Variant names:

• chr12-53328189-G-A
• rs777225684
• NM_001173467.3:c.1253C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-53328189-G-A
• chr12-53328189-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001173467.3(SP7):​c.1253C>T​(p.Ala418Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A418D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SP7 NM_001173467.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.850
• Publications: 1 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07241997).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SP7	NM_001173467.3	MANE Select	c.1253C>T	p.Ala418Val	missense	Exon 3 of 3	NP_001166938.1	Q8TDD2-1
	SP7	NM_152860.2		c.1253C>T	p.Ala418Val	missense	Exon 2 of 2	NP_690599.1	Q8TDD2-1
	SP7	NM_001300837.2		c.1199C>T	p.Ala400Val	missense	Exon 3 of 3	NP_001287766.1	Q8TDD2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SP7	ENST00000536324.4	TSL:2 MANE Select	c.1253C>T	p.Ala418Val	missense	Exon 3 of 3	ENSP00000443827.2	Q8TDD2-1
	SP7	ENST00000303846.3	TSL:1	c.1253C>T	p.Ala418Val	missense	Exon 2 of 2	ENSP00000302812.3	Q8TDD2-1
	SP7	ENST00000537210.2	TSL:1	c.1199C>T	p.Ala400Val	missense	Exon 2 of 2	ENSP00000441367.2	Q8TDD2-2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000816 AC: 2 AN: 245212 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1460840 Hom.: 0 Cov.: 29 AF XY: 0.00000550 AC XY: 4 AN XY: 726694

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111652

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.85
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.032
Sift	Uncertain	0.021	D
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.36		Loss of glycosylation at P415 (P = 0.1098)
MVP		0.043
MPC		0.33
ClinPred		0.094	T
GERP RS		0.055
Varity_R		0.11
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs777225684; hg19: chr12-53721973; COSMIC: COSV58190829; COSMIC: COSV58190829;