12-53328087-T-A

Variant names:

• chr12-53328087-T-A
• rs140159335
• NM_001173467.3:c.*59A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001173467.3(SP7):​c.*59A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,477,294 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (15 hom., cov: 32)
  • Exomes 𝑓: 0.014 (211 hom.)
• Consequence: SP7 NM_001173467.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.04
• Publications: 4 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-53328087-T-A is Benign according to our data. Variant chr12-53328087-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 309759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0094 (1429/152098) while in subpopulation SAS AF = 0.0404 (194/4804). AF 95% confidence interval is 0.0357. There are 15 homozygotes in GnomAd4. There are 690 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AD,AR gene

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.*59A>T		3_prime_UTR	Exon 3 of 3	NP_001166938.1	Q8TDD2-1
	SP7	NM_152860.2		c.*59A>T		3_prime_UTR	Exon 2 of 2	NP_690599.1	Q8TDD2-1
	SP7	NM_001300837.2		c.*59A>T		3_prime_UTR	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.*59A>T		3_prime_UTR	Exon 3 of 3	ENSP00000443827.2	Q8TDD2-1
	SP7	ENST00000303846.3	TSL:1	c.*59A>T		3_prime_UTR	Exon 2 of 2	ENSP00000302812.3	Q8TDD2-1
	SP7	ENST00000537210.2	TSL:1	c.*59A>T		downstream_gene	N/A	ENSP00000441367.2	Q8TDD2-2

Frequencies

GnomAD3 genomes AF: 0.00941 AC: 1430 AN: 151982 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00235

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00852

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0403

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.00766

GnomAD4 exome AF: 0.0139 AC: 18388 AN: 1325196 Hom.: 211 Cov.: 22 AF XY: 0.0147 AC XY: 9576 AN XY: 652060

African (AFR) AF: 0.00196 AC: 58 AN: 29588

American (AMR) AF: 0.00712 AC: 192 AN: 26972

Ashkenazi Jewish (ASJ) AF: 0.00954 AC: 201 AN: 21062

East Asian (EAS) AF: 0.000111 AC: 4 AN: 36172

South Asian (SAS) AF: 0.0428 AC: 3034 AN: 70850

European-Finnish (FIN) AF: 0.00207 AC: 93 AN: 44862

Middle Eastern (MID) AF: 0.0270 AC: 145 AN: 5366

European-Non Finnish (NFE) AF: 0.0134 AC: 13916 AN: 1035350

Other (OTH) AF: 0.0136 AC: 745 AN: 54974

GnomAD4 genome AF: 0.00940 AC: 1429 AN: 152098 Hom.: 15 Cov.: 32 AF XY: 0.00928 AC XY: 690 AN XY: 74364

African (AFR) AF: 0.00234 AC: 97 AN: 41482

American (AMR) AF: 0.00851 AC: 130 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0404 AC: 194 AN: 4804

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10610

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0138 AC: 939 AN: 67964

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00974 Hom.: 1

Bravo AF: 0.00919

Asia WGS AF: 0.0140 AC: 47 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	10
DANN	Benign	0.71
PhyloP100		-1.0
Mutation Taster		=97/3	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: rs140159335; hg19: chr12-53721871; COSMIC: COSV107335204; COSMIC: COSV107335204;