chr7-21428754-G-A

Variant names:

• chr7-21428754-G-A
• NM_003112.5:c.85G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003112.5(SP4):​c.85G>A​(p.Glu29Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,400,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. E29Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SP4 NM_003112.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.42
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27958333).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003112.5. 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
	SP4	NM_003112.5	MANE Select	c.85G>A	p.Glu29Lys	missense	Exon 2 of 6	NP_003103.2	Q02446
	SP4	NM_001326542.2		c.34G>A	p.Glu12Lys	missense	Exon 2 of 6	NP_001313471.1	A0A3B3IRW4
	SP4	NM_001326543.2		c.-821G>A		5_prime_UTR	Exon 2 of 6	NP_001313472.1	Q32M51

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SP4	ENST00000222584.8	TSL:1 MANE Select	c.85G>A	p.Glu29Lys	missense	Exon 2 of 6	ENSP00000222584.3	Q02446
	SP4	ENST00000959244.1		c.85G>A	p.Glu29Lys	missense	Exon 2 of 6	ENSP00000629303.1
	SP4	ENST00000649633.1		c.34G>A	p.Glu12Lys	missense	Exon 2 of 6	ENSP00000496957.1	A0A3B3IRW4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1400236 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 690784

African (AFR) AF: 0.00 AC: 0 AN: 31568

American (AMR) AF: 0.00 AC: 0 AN: 35686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35810

South Asian (SAS) AF: 0.00 AC: 0 AN: 79226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1079588

Other (OTH) AF: 0.00 AC: 0 AN: 58070

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	0.23
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		7.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.16
Sift	Uncertain	0.017	D
Sift4G	Benign	0.65	T
Polyphen		0.74	P
Vest4		0.28
MutPred		0.17		Gain of MoRF binding (P = 0.0065)
MVP		0.14
MPC		0.28
ClinPred		0.85	D
GERP RS		4.7
Varity_R		0.24
gMVP		0.36
Mutation Taster		=92/8	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

hg19: chr7-21468372;