4-1167501-C-T

Variant names:

• chr4-1167501-C-T
• rs1430494473
• NM_012445.4:c.967G>A

Variant summary

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

The NM_012445.4(SPON2):​c.967G>A​(p.Ala323Thr) 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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPON2 NM_012445.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.490

Genes affected

SPON2 (HGNC:11253): (spondin 2) Predicted to enable antigen binding activity; lipopolysaccharide binding activity; and metal ion binding activity. Predicted to be involved in cell adhesion. Predicted to act upstream of or within several processes, including defense response to other organism; opsonization; and positive regulation of cytokine production. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

LOC124900647 (HGNC:):

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=0.036288947).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPON2	NM_012445.4	c.967G>A	p.Ala323Thr	missense_variant	Exon 6 of 6	ENST00000290902.10	NP_036577.2
SPON2	NM_001128325.3	c.967G>A	p.Ala323Thr	missense_variant	Exon 7 of 7		NP_001121797.2
SPON2	NM_001199021.2	c.967G>A	p.Ala323Thr	missense_variant	Exon 8 of 8		NP_001185950.2
LOC124900647	XM_047416477.1	c.-2486-23599C>T		intron_variant	Intron 1 of 2		XP_047272433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPON2	ENST00000290902.10	c.967G>A	p.Ala323Thr	missense_variant	Exon 6 of 6	1	NM_012445.4	ENSP00000290902.5
SPON2	ENST00000431380.5	c.967G>A	p.Ala323Thr	missense_variant	Exon 7 of 7	5		ENSP00000394832.1
SPON2	ENST00000617421.4	c.967G>A	p.Ala323Thr	missense_variant	Exon 8 of 8	5		ENSP00000483599.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.967G>A (p.A323T) alteration is located in exon 8 (coding exon 5) of the SPON2 gene. This alteration results from a G to A substitution at nucleotide position 967, causing the alanine (A) at amino acid position 323 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	0.063
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Benign	0.96
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.24	N
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.036	T;T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.58	N;N;.
REVEL	Benign	0.026
Sift	Benign	0.54	T;T;.
Sift4G	Benign	0.59	T;T;T
Vest4		0.066
MutPred		0.29		Gain of catalytic residue at E322 (P = 0.5037);Gain of catalytic residue at E322 (P = 0.5037);Gain of catalytic residue at E322 (P = 0.5037);
MVP		0.081
MPC		0.23
ClinPred		0.12	T
GERP RS		-0.66
gMVP		0.42

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: rs1430494473; hg19: chr4-1161289;