Genetic Variant SP3:p.His575His (chr2-173918700-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_003111.5(SP3):c.1725C>T(p.His575His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000374 in 1,613,624 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

SP3
NM_003111.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.762

Variant links:

Genes affected

SP3 (HGNC:11208): (Sp3 transcription factor) This gene belongs to a family of Sp1 related genes that encode transcription factors that regulate transcription by binding to consensus GC- and GT-box regulatory elements in target genes. This protein contains a zinc finger DNA-binding domain and several transactivation domains, and has been reported to function as a bifunctional transcription factor that either stimulates or represses the transcription of numerous genes. Transcript variants encoding different isoforms have been described for this gene, and one has been reported to initiate translation from a non-AUG (AUA) start codon. Additional isoforms, resulting from the use of alternate downstream translation initiation sites, have also been noted. A related pseudogene has been identified on chromosome 13. [provided by RefSeq, Feb 2010]

SP3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 2-173918700-G-A is Benign according to our data. Variant chr2-173918700-G-A is described in ClinVar as [Benign]. Clinvar id is 716904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.762 with no splicing effect.

BS2

High AC in GnomAd4 at 216 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SP3	NM_003111.5 link	c.1725C>T	p.His575His	synonymous_variant	Exon 5 of 7	ENST00000310015.12	NP_003102.1	Q02447-1Q86TP0
SP3	NM_001172712.1 link	c.1716C>T	p.His572His	synonymous_variant	Exon 5 of 7		NP_001166183.1	Q02447Q59FX5B7ZLN9
SP3	NM_001017371.5 link	c.1521C>T	p.His507His	synonymous_variant	Exon 3 of 5		NP_001017371.3	Q02447-5Q59FX5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SP3	ENST00000310015.12 link	c.1725C>T	p.His575His	synonymous_variant	Exon 5 of 7	1	NM_003111.5	ENSP00000310301.6		Q02447-1

Frequencies

GnomAD3 genomes

AF:

0.00142

AC:

215

AN:

151908

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00433

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000788

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:

0.000309

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000420

AC:

105

AN:

250168

Hom.:

AF XY:

0.000311

AC XY:

AN XY:

135208

show subpopulations

Gnomad AFR exome

AF:

0.00382

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000222

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000265

AC:

387

AN:

1461598

Hom.:

Cov.:

AF XY:

0.000246

AC XY:

179

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.00397

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000152

Gnomad4 OTH exome

AF:

0.000845

GnomAD4 genome

AF:

0.00142

AC:

216

AN:

152026

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

104

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00434

Gnomad4 AMR

AF:

0.000787

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000900

Hom.:

Bravo

AF:

0.00168

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

2.2

DANN

Benign

0.54

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over