12-21526958-G-C

Position:

• chr12-21526958-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030572.4(SPX):​c.79G>C​(p.Ala27Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPX NM_030572.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.24

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPX	NM_030572.4	c.79G>C	p.Ala27Pro	missense_variant	2/6	ENST00000256969.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPX	ENST00000256969.7	c.79G>C	p.Ala27Pro	missense_variant	2/6	1	NM_030572.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251436 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2022

The c.79G>C (p.A27P) alteration is located in exon 2 (coding exon 2) of the SPX gene. This alteration results from a G to C substitution at nucleotide position 79, causing the alanine (A) at amino acid position 27 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.046
Eigen_PC	Benign	-0.071
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0083	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	N
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.24
Sift	Benign	0.080	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.72
MutPred		0.40		Gain of catalytic residue at A27 (P = 0);
MVP		0.36
MPC		1.1
ClinPred		0.96	D
GERP RS		3.9
Varity_R		0.66
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs780278792; hg19: chr12-21679892;