16-89850382-C-T

Variant summary

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

The NM_032451.2(SPIRE2):c.367C>T(p.Pro123Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,447,052 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P123L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SPIRE2 NM_032451.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.33

Genes affected

SPIRE2 (HGNC:30623): (spire type actin nucleation factor 2) Predicted to enable actin binding activity. Involved in establishment of meiotic spindle localization; formin-nucleated actin cable assembly; and positive regulation of double-strand break repair. Predicted to be located in cytoskeleton; cytosol; and plasma membrane. Predicted to be active in cell cortex and cytoplasmic vesicle membrane. Predicted to colocalize with cleavage furrow. [provided by Alliance of Genome Resources, Apr 2022]

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
SPIRE2	NM_032451.2	c.367C>T	p.Pro123Ser	missense_variant	3/15	ENST00000378247.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPIRE2	ENST00000378247.8	c.367C>T	p.Pro123Ser	missense_variant	3/15	1	NM_032451.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447052 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718728

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: 0.00000181

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Jan 31, 2024

The c.367C>T (p.P123S) alteration is located in exon 3 (coding exon 3) of the SPIRE2 gene. This alteration results from a C to T substitution at nucleotide position 367, causing the proline (P) at amino acid position 123 to be replaced by a serine (S). 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	0.29
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Benign	0.18
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		1.0	D;D
Vest4		0.59
MutPred		0.21		Gain of phosphorylation at P123 (P = 0.043);Gain of phosphorylation at P123 (P = 0.043);
MVP		0.38
MPC		0.67
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs1291356436; hg19: chr16-89916790;