15-88856963-T-C

Variant names:

• chr15-88856963-T-C
• NM_001369268.1:c.4378T>C

Variant summary

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

The NM_001369268.1(ACAN):​c.4378T>C​(p.Ser1460Pro) 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. 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. S1460A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACAN NM_001369268.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.124
• Publications: 0 publications found

Genes affected

ACAN (HGNC:319): (aggrecan) This gene is a member of the aggrecan/versican proteoglycan family. The encoded protein is an integral part of the extracellular matrix in cartilagenous tissue and it withstands compression in cartilage. Mutations in this gene may be involved in skeletal dysplasia and spinal degeneration. Multiple alternatively spliced transcript variants that encode different protein isoforms have been observed in this gene. [provided by RefSeq, Jul 2008]

ACAN Gene-Disease associations (from GenCC):

• osteochondritis dissecans

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• spondyloepiphyseal dysplasia, Kimberley type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• spondyloepimetaphyseal dysplasia, aggrecan type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• short stature-advanced bone age-early-onset osteoarthritis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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=0.23778248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAN	NM_001369268.1	c.4378T>C	p.Ser1460Pro	missense_variant	Exon 12 of 19	ENST00000560601.4	NP_001356197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAN	ENST00000560601.4	c.4378T>C	p.Ser1460Pro	missense_variant	Exon 12 of 19	3	NM_001369268.1	ENSP00000453581.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	15
DANN	Uncertain	0.99
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.66	T;T;T;T;T;.
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.24	T;T;T;T;T;T
MetaSVM	Uncertain	0.35	D
PhyloP100		-0.12
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	.;N;.;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.039	.;D;.;D;D;D
Sift4G	Benign	0.21	.;T;T;T;T;T
Vest4		0.34, 0.23, 0.16, 0.19, 0.39
MutPred		0.17		Loss of glycosylation at S1460 (P = 0.0224);Loss of glycosylation at S1460 (P = 0.0224);.;Loss of glycosylation at S1460 (P = 0.0224);Loss of glycosylation at S1460 (P = 0.0224);Loss of glycosylation at S1460 (P = 0.0224);
MVP		0.29
MPC		0.32
ClinPred		0.22	T
GERP RS		2.4
Varity_R		0.21
gMVP		0.13

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

hg19: chr15-89400194;