Genetic Variant SP4:c.1678+75A>T (chr7-21430918-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003112.5(SP4):c.1678+75A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 1,144,758 control chromosomes in the GnomAD database, including 271,385 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.73 ( 41785 hom., cov: 33)

Exomes 𝑓: 0.68 ( 229600 hom. )

Consequence

SP4
NM_003112.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.408

Publications

13 publications found

Variant links:

Genes affected

SP4 (HGNC:11209): (Sp4 transcription factor) The protein encoded by this gene is a transcription factor that can bind to the GC promoter region of a variety of genes, including those of the photoreceptor signal transduction system. The encoded protein binds to the same sites in promoter CpG islands as does the transcription factor SP1, although its expression is much more restricted compared to that of SP1. This gene may be involved in bipolar disorder and schizophrenia. [provided by RefSeq, May 2016]

SP4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SP4	NM_003112.5 link	c.1678+75A>T		intron_variant	Intron 3 of 5	ENST00000222584.8	NP_003103.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
SP4	ENST00000222584.8 link	c.1678+75A>T	intron_variant	Intron 3 of 5	1	NM_003112.5	ENSP00000222584.3
SP4	ENST00000649633.1 link	c.1627+75A>T	intron_variant	Intron 3 of 5			ENSP00000496957.1
SP4	ENST00000432066.2 link	c.7+2660A>T	intron_variant	Intron 1 of 1	5		ENSP00000393623.2
SP4	ENST00000448246.1 link	n.123+2126A>T	intron_variant	Intron 2 of 4	5		ENSP00000390817.1

Frequencies

GnomAD3 genomes

AF:

0.732

AC:

111370

AN:

152070

Hom.:

41732

Cov.:

show subpopulations

Gnomad AFR

AF:

0.888

Gnomad AMI

AF:

0.635

Gnomad AMR

AF:

0.718

Gnomad ASJ

AF:

0.678

Gnomad EAS

AF:

0.919

Gnomad SAS

AF:

0.738

Gnomad FIN

AF:

0.632

Gnomad MID

AF:

0.772

Gnomad NFE

AF:

0.647

Gnomad OTH

AF:

0.705

GnomAD4 exome

AF:

0.676

AC:

670896

AN:

992570

Hom.:

229600

AF XY:

0.677

AC XY:

339882

AN XY:

501932

show subpopulations

African (AFR)

AF:

0.898

AC:

21264

AN:

23668

American (AMR)

AF:

0.723

AC:

21816

AN:

30176

Ashkenazi Jewish (ASJ)

AF:

0.684

AC:

12439

AN:

18196

East Asian (EAS)

AF:

0.933

AC:

34925

AN:

37418

South Asian (SAS)

AF:

0.722

AC:

45349

AN:

62830

European-Finnish (FIN)

AF:

0.630

AC:

22415

AN:

35588

Middle Eastern (MID)

AF:

0.763

AC:

3520

AN:

4616

European-Non Finnish (NFE)

AF:

0.650

AC:

478264

AN:

735488

Other (OTH)

AF:

0.693

AC:

30904

AN:

44590

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

11098

22197

33295

44394

55492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11124

22248

33372

44496

55620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.733

AC:

111479

AN:

152188

Hom.:

41785

Cov.:

AF XY:

0.734

AC XY:

54625

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.888

AC:

36887

AN:

41540

American (AMR)

AF:

0.718

AC:

10977

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.678

AC:

2354

AN:

3470

East Asian (EAS)

AF:

0.919

AC:

4774

AN:

5192

South Asian (SAS)

AF:

0.739

AC:

3566

AN:

4828

European-Finnish (FIN)

AF:

0.632

AC:

6683

AN:

10582

Middle Eastern (MID)

AF:

0.776

AC:

228

AN:

294

European-Non Finnish (NFE)

AF:

0.647

AC:

43948

AN:

67970

Other (OTH)

AF:

0.703

AC:

1483

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1484

2968

4452

5936

7420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

834

1668

2502

3336

4170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.689

Hom.:

4528

Bravo

AF:

0.745

Asia WGS

AF:

0.806

AC:

2802

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.2

(source)

DANN

Benign

0.49

PhyloP100

-0.41

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over