9-92465001-A-T

Variant summary

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

The ENST00000375544.7(ASPN):c.630T>A(p.Asn210Lys) 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. 15/19 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: ASPN ENST00000375544.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.350

Genes affected

ASPN (HGNC:14872): (asporin) This gene encodes a cartilage extracellular protein that is member of the small leucine-rich proteoglycan family. The encoded protein may regulate chondrogenesis by inhibiting transforming growth factor-beta 1-induced gene expression in cartilage. This protein also binds collagen and calcium and may induce collagen mineralization. Polymorphisms in the aspartic acid repeat region of this gene are associated with a susceptibility to osteoarthritis, and also with intervertebral disc disease. Alternative splicing of this gene results in multiple transcript variants.[provided by RefSeq, Jul 2014]

CENPP (HGNC:32933): (centromere protein P) CENPP is a subunit of a CENPH (MIM 605607)-CENPI (MIM 300065)-associated centromeric complex that targets CENPA (MIM 117139) to centromeres and is required for proper kinetochore function and mitotic progression (Okada et al., 2006 [PubMed 16622420]).[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=0.14903823).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPN	NM_017680.6	c.630T>A	p.Asn210Lys	missense_variant	5/8	ENST00000710274.1
ASPN	NM_001193335.3	c.630T>A	p.Asn210Lys	missense_variant	5/6
CENPP	NM_001012267.3	c.564+85142A>T		intron_variant		ENST00000375587.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPN	ENST00000375544.7	c.630T>A	p.Asn210Lys	missense_variant	5/8	1		P1
CENPP	ENST00000375587.8	c.564+85142A>T		intron_variant		1	NM_001012267.3	P1
ASPN	ENST00000375543.2	c.630T>A	p.Asn210Lys	missense_variant	5/6	2
ASPN	ENST00000650794.1	c.388-4467T>A		intron_variant, NMD_transcript_variant

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

The c.627T>A (p.N209K) alteration is located in exon 5 (coding exon 4) of the ASPN gene. This alteration results from a T to A substitution at nucleotide position 627, causing the asparagine (N) at amino acid position 209 to be replaced by a lysine (K). 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	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.072	T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.79	T;D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.035	N;.
MutationTaster	Benign	0.61	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.064
Sift	Benign	0.17	T;D
Sift4G	Benign	0.55	T;T
Polyphen		0.010	B;B
Vest4		0.31
MutPred		0.52		Gain of ubiquitination at N210 (P = 0.0077);Gain of ubiquitination at N210 (P = 0.0077);
MVP		0.61
MPC		0.23
ClinPred		0.47	T
GERP RS		-0.011
Varity_R		0.072

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: chr9-95227283;