12-21527777-C-G

Variant names:

• chr12-21527777-C-G
• rs772766676
• NM_030572.4:c.196C>G

Variant summary

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

The NM_030572.4(SPX):​c.196C>G​(p.Arg66Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,418,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R66Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SPX NM_030572.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.80
• Publications: 0 publications found

Genes affected

SPX (HGNC:28139): (spexin hormone) The protein encoded by this gene is a hormone involved in modulation of cardiovascular and renal function. It has also been shown in rats to cause weight loss. Several transcript variants have been found for this gene. [provided by RefSeq, Feb 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=0.30097002).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030572.4. 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
	SPX	NM_030572.4	MANE Select	c.196C>G	p.Arg66Gly	missense	Exon 4 of 6	NP_085049.1	Q9BT56
	SPX	NR_135187.2		n.247C>G		non_coding_transcript_exon	Exon 1 of 3
	SPX	NR_135188.2		n.-175C>G		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPX	ENST00000256969.7	TSL:1 MANE Select	c.196C>G	p.Arg66Gly	missense	Exon 4 of 6	ENSP00000256969.2	Q9BT56
	SPX	ENST00000535139.5	TSL:1	n.343C>G		non_coding_transcript_exon	Exon 1 of 3
	SPX	ENST00000535033.5	TSL:2	c.73C>G	p.Arg25Gly	missense	Exon 2 of 4	ENSP00000497284.1	A0A3B3ISF3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418728 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 701170

African (AFR) AF: 0.00 AC: 0 AN: 32960

American (AMR) AF: 0.00 AC: 0 AN: 37174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25284

East Asian (EAS) AF: 0.00 AC: 0 AN: 38178

South Asian (SAS) AF: 0.00 AC: 0 AN: 80636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089744

Other (OTH) AF: 0.00 AC: 0 AN: 58828

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.022
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.8
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.16
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.18		Gain of ubiquitination at K61 (P = 0.0204)
MVP		0.21
MPC		1.1
ClinPred		0.99	D
GERP RS		2.7
Varity_R		0.23
gMVP		0.24
Mutation Taster		=96/4	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: rs772766676; hg19: chr12-21680711;