18-12464880-A-T

Position:

• chr18-12464880-A-T

Variant summary

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

The NM_001128626.2(SPIRE1):​c.1483T>A​(p.Ser495Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SPIRE1 NM_001128626.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.598

Genes affected

SPIRE1 (HGNC:30622): (spire type actin nucleation factor 1) Spire proteins, such as SPIRE1, are highly conserved between species. They belong to the family of Wiskott-Aldrich homology region-2 (WH2) proteins, which are involved in actin organization (Kerkhoff et al., 2001 [PubMed 11747823]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062918484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPIRE1	NM_001128626.2	c.1483T>A	p.Ser495Thr	missense_variant	11/17	ENST00000409402.9	NP_001122098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPIRE1	ENST00000409402.9	c.1483T>A	p.Ser495Thr	missense_variant	11/17	1	NM_001128626.2	ENSP00000387266	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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

Feb 28, 2024

The c.1483T>A (p.S495T) alteration is located in exon 11 (coding exon 11) of the SPIRE1 gene. This alteration results from a T to A substitution at nucleotide position 1483, causing the serine (S) at amino acid position 495 to be replaced by a threonine (T). 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	0.064
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.9
DANN	Benign	0.43
DEOGEN2	Benign	0.032	T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.62	T;T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.063	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.35	N;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.37	T;T;T;T
Sift4G	Benign	0.57	T;T;T;T
Polyphen		0.0080	B;B;.;.
Vest4		0.096
MutPred		0.33		Gain of glycosylation at T496 (P = 0.1028);.;.;.;
MVP		0.30
MPC		0.32
ClinPred		0.023	T
GERP RS		-1.8
Varity_R		0.026
gMVP		0.10

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: chr18-12464879;