12-21527778-G-A

Position:

• chr12-21527778-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030572.4(SPX):​c.197G>A​(p.Arg66Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000564 in 1,418,826 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: SPX NM_030572.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.10

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2638035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPX	NM_030572.4	c.197G>A	p.Arg66Gln	missense_variant	4/6	ENST00000256969.7	NP_085049.1
SPX	NR_135187.2	n.248G>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPX	ENST00000256969.7	c.197G>A	p.Arg66Gln	missense_variant	4/6	1	NM_030572.4	ENSP00000256969.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000564 AC: 8 AN: 1418826 Hom.: 0 Cov.: 31 AF XY: 0.00000285 AC XY: 2 AN XY: 701224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000734

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Sep 04, 2024

The c.197G>A (p.R66Q) alteration is located in exon 4 (coding exon 4) of the SPX gene. This alteration results from a G to A substitution at nucleotide position 197, causing the arginine (R) at amino acid position 66 to be replaced by a glutamine (Q). 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	0.10
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	2.0	M;.
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.10
Sift	Uncertain	0.029	D;.
Sift4G	Benign	0.064	T;.
Polyphen		1.0	D;.
Vest4		0.48
MutPred		0.14		Gain of ubiquitination at K61 (P = 0.0192);.;
MVP		0.10
MPC		1.0
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.23
gMVP		0.19

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-21680712;