11-13963004-C-A

Variant names:

• chr11-13963004-C-A
• rs373585962
• NM_006108.4:c.100C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006108.4(SPON1):​c.100C>A​(p.Leu34Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L34V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SPON1 NM_006108.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.374
• Publications: 0 publications found

Genes affected

SPON1 (HGNC:11252): (spondin 1) Predicted to be an extracellular matrix structural constituent. Predicted to be involved in cell adhesion. Predicted to act upstream of or within positive regulation of protein binding activity; positive regulation of protein processing; and regulation of amyloid precursor protein catabolic process. Located in extracellular space. Colocalizes with collagen-containing extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

LOC124902637 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11971435).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006108.4. 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
	SPON1	NM_006108.4	MANE Select	c.100C>A	p.Leu34Met	missense	Exon 1 of 16	NP_006099.2	Q9HCB6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPON1	ENST00000576479.4	TSL:1 MANE Select	c.100C>A	p.Leu34Met	missense	Exon 1 of 16	ENSP00000460236.1	Q9HCB6
	SPON1	ENST00000964987.1		c.100C>A	p.Leu34Met	missense	Exon 1 of 16	ENSP00000635046.1
	SPON1	ENST00000883678.1		c.100C>A	p.Leu34Met	missense	Exon 1 of 15	ENSP00000553737.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442220 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 716072

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32550

American (AMR) AF: 0.00 AC: 0 AN: 42828

Ashkenazi Jewish (ASJ) AF: 0.0000389 AC: 1 AN: 25710

East Asian (EAS) AF: 0.00 AC: 0 AN: 38312

South Asian (SAS) AF: 0.00 AC: 0 AN: 83024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103650

Other (OTH) AF: 0.00 AC: 0 AN: 59614

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.37
PrimateAI	Uncertain	0.73	T
Sift4G	Benign	0.073	T
Polyphen		0.26	B
Vest4		0.29
MutPred		0.19		Gain of methylation at K39 (P = 0.0615)
MVP		0.33
ClinPred		0.77	D
GERP RS		5.2
PromoterAI		0.099	Neutral
Varity_R		0.26
gMVP		0.30

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: rs373585962; hg19: chr11-13984551;