15-88856926-G-T

Variant names:

• chr15-88856926-G-T
• rs201505307
• NM_001369268.1:c.4341G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001369268.1(ACAN):​c.4341G>T​(p.Glu1447Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,568,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1447K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: ACAN NM_001369268.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.07
• Publications: 3 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):

• ACAN-related short stature spectrum

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• osteochondritis dissecans

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040175796).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369268.1. 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
	ACAN	NM_001369268.1	MANE Select	c.4341G>T	p.Glu1447Asp	missense	Exon 12 of 19	NP_001356197.1	P16112-4
	ACAN	NM_001411097.1		c.4341G>T	p.Glu1447Asp	missense	Exon 12 of 18	NP_001398026.1	A0A5K1VW97
	ACAN	NM_013227.4		c.4341G>T	p.Glu1447Asp	missense	Exon 12 of 18	NP_037359.3	P16112-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAN	ENST00000560601.4	TSL:3 MANE Select	c.4341G>T	p.Glu1447Asp	missense	Exon 12 of 19	ENSP00000453581.2	P16112-4
	ACAN	ENST00000439576.7	TSL:5	c.4341G>T	p.Glu1447Asp	missense	Exon 12 of 18	ENSP00000387356.2	P16112-1
	ACAN	ENST00000561243.7	TSL:5	c.4341G>T	p.Glu1447Asp	missense	Exon 12 of 18	ENSP00000453342.3	A0A5K1VW97

Frequencies

GnomAD3 genomes AF: 0.0000153 AC: 2 AN: 131112 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000334

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000264 AC: 38 AN: 1437260 Hom.: 0 Cov.: 42 AF XY: 0.0000196 AC XY: 14 AN XY: 715376

African (AFR) AF: 0.00 AC: 0 AN: 32484

American (AMR) AF: 0.00 AC: 0 AN: 43542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24992

East Asian (EAS) AF: 0.00 AC: 0 AN: 38546

South Asian (SAS) AF: 0.00 AC: 0 AN: 85242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5416

European-Non Finnish (NFE) AF: 0.0000338 AC: 37 AN: 1095764

Other (OTH) AF: 0.0000171 AC: 1 AN: 58508

GnomAD4 genome AF: 0.0000153 AC: 2 AN: 131112 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 64586

African (AFR) AF: 0.00 AC: 0 AN: 34458

American (AMR) AF: 0.00 AC: 0 AN: 13698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3140

East Asian (EAS) AF: 0.00 AC: 0 AN: 4148

South Asian (SAS) AF: 0.00 AC: 0 AN: 3942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 184

European-Non Finnish (NFE) AF: 0.0000334 AC: 2 AN: 59866

Other (OTH) AF: 0.00 AC: 0 AN: 1818

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.0010
DANN	Benign	0.22
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.64	T
PhyloP100		-4.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.26
Sift	Benign	0.54	T
Sift4G	Benign	0.63	T
Vest4		0.029
MutPred		0.27		Loss of phosphorylation at S1449 (P = 0.3149)
MVP		0.14
MPC		0.18
ClinPred		0.038	T
GERP RS		-5.3
Varity_R		0.032
gMVP		0.055
Mutation Taster		=100/0	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: rs201505307; hg19: chr15-89400157;