18-12479868-A-G

Position:

• chr18-12479868-A-G

Variant summary

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

The NM_001128626.2(SPIRE1):​c.1235T>C​(p.Val412Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPIRE1 NM_001128626.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44

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 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=0.1662274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPIRE1	NM_001128626.2	c.1235T>C	p.Val412Ala	missense_variant	10/17	ENST00000409402.9	NP_001122098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPIRE1	ENST00000409402.9	c.1235T>C	p.Val412Ala	missense_variant	10/17	1	NM_001128626.2	ENSP00000387266	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

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

Apr 29, 2024

The c.1235T>C (p.V412A) alteration is located in exon 10 (coding exon 10) of the SPIRE1 gene. This alteration results from a T to C substitution at nucleotide position 1235, causing the valine (V) at amino acid position 412 to be replaced by an alanine (A). 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	0.11
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.036	T;.;T;.
Eigen	Benign	0.090
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.59	T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.3	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.63	N;N;N;N
REVEL	Benign	0.094
Sift	Benign	0.24	T;T;T;T
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.98	D;B;.;.
Vest4		0.37
MutPred		0.39		Loss of stability (P = 0.0507);.;.;.;
MVP		0.63
MPC		0.72
ClinPred		0.46	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.053
gMVP		0.21

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: rs1210996806; hg19: chr18-12479867;