7-21429670-C-G

Variant names:

• chr7-21429670-C-G
• rs1051112589
• NM_003112.5:c.505C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001326543.2(SP4):​c.-435C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SP4 NM_001326543.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SP4	NM_003112.5	c.505C>G	p.Pro169Ala	missense_variant	Exon 3 of 6	ENST00000222584.8	NP_003103.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SP4	ENST00000222584.8	c.505C>G	p.Pro169Ala	missense_variant	Exon 3 of 6	1	NM_003112.5	ENSP00000222584.3
SP4	ENST00000649633.1	c.454C>G	p.Pro152Ala	missense_variant	Exon 3 of 6			ENSP00000496957.1
SP4	ENST00000432066.2	c.7+1412C>G		intron_variant	Intron 1 of 1	5		ENSP00000393623.2
SP4	ENST00000448246.1	n.123+878C>G		intron_variant	Intron 2 of 4	5		ENSP00000390817.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.1	D;.
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.43		Loss of catalytic residue at P169 (P = 0.0654);.;
MVP		0.63
MPC		0.29
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.73
gMVP		0.45

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: rs1051112589; hg19: chr7-21469288;