4-1170414-C-T

Variant names:

• chr4-1170414-C-T
• rs370208822
• NM_012445.4:c.799G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012445.4(SPON2):​c.799G>A​(p.Asp267Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: SPON2 NM_012445.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3134721).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012445.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPON2	NM_012445.4	MANE Select	c.799G>A	p.Asp267Asn	missense	Exon 5 of 6	NP_036577.2	Q9BUD6
	SPON2	NM_001128325.3		c.799G>A	p.Asp267Asn	missense	Exon 6 of 7	NP_001121797.2	Q9BUD6
	SPON2	NM_001199021.2		c.799G>A	p.Asp267Asn	missense	Exon 7 of 8	NP_001185950.2	Q9BUD6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPON2	ENST00000290902.10	TSL:1 MANE Select	c.799G>A	p.Asp267Asn	missense	Exon 5 of 6	ENSP00000290902.5	Q9BUD6
	SPON2	ENST00000960395.1		c.1123G>A	p.Asp375Asn	missense	Exon 5 of 6	ENSP00000630454.1
	SPON2	ENST00000431380.5	TSL:5	c.799G>A	p.Asp267Asn	missense	Exon 6 of 7	ENSP00000394832.1	Q9BUD6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249346 AF XY: 0.00000742

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000500 AC: 73 AN: 1461158 Hom.: 0 Cov.: 30 AF XY: 0.0000468 AC XY: 34 AN XY: 726872

African (AFR) AF: 0.0000897 AC: 3 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000630 AC: 70 AN: 1111794

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74358

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.12
Sift	Benign	0.051	T
Sift4G	Benign	0.12	T
Vest4		0.28
MVP		0.53
MPC		0.25
ClinPred		0.36	T
GERP RS		4.7
gMVP		0.43
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs370208822; hg19: chr4-1164202;