12-21531137-A-C

Position:

• chr12-21531137-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_030572.4(SPX):​c.293A>C​(p.Asp98Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SPX NM_030572.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001218
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.422

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029536426).
• BP6: Variant 12-21531137-A-C is Benign according to our data. Variant chr12-21531137-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3169772.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPX	NM_030572.4	c.293A>C	p.Asp98Ala	missense_variant, splice_region_variant	6/6	ENST00000256969.7
SPX	NR_135187.2	n.344A>C		splice_region_variant, non_coding_transcript_exon_variant	3/3
SPX	NR_135188.2	n.285A>C		splice_region_variant, non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPX	ENST00000256969.7	c.293A>C	p.Asp98Ala	missense_variant, splice_region_variant	6/6	1	NM_030572.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1414590 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 704794

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: 0.00

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.79
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.030	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.46	N;.
MutationTaster	Benign	0.97	N
PROVEAN	Uncertain	-2.7	D;.
REVEL	Benign	0.13
Sift	Benign	0.49	T;.
Sift4G	Benign	0.75	T;.
Polyphen		0.0	B;.
Vest4		0.056
MutPred		0.090		Loss of loop (P = 0.1258);.;
MVP		0.088
MPC		0.35
ClinPred		0.030	T
GERP RS		-4.5
Varity_R		0.087
gMVP		0.055

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.020		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: rs1943861571; hg19: chr12-21684071;