chr15-88855595-A-T

Variant names:

• chr15-88855595-A-T
• rs34570487
• NM_001369268.1:c.3010A>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.3010A>T​(p.Thr1004Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T1004A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 8)
  • Exomes 𝑓: 0.00019 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACAN NM_001369268.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.266
• Publications: 6 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031533152).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAN	NM_001369268.1	MANE Select	c.3010A>T	p.Thr1004Ser	missense	Exon 12 of 19	NP_001356197.1
	ACAN	NM_001411097.1		c.3010A>T	p.Thr1004Ser	missense	Exon 12 of 18	NP_001398026.1
	ACAN	NM_013227.4		c.3010A>T	p.Thr1004Ser	missense	Exon 12 of 18	NP_037359.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAN	ENST00000560601.4	TSL:3 MANE Select	c.3010A>T	p.Thr1004Ser	missense	Exon 12 of 19	ENSP00000453581.2
	ACAN	ENST00000439576.7	TSL:5	c.3010A>T	p.Thr1004Ser	missense	Exon 12 of 18	ENSP00000387356.2
	ACAN	ENST00000561243.7	TSL:5	c.3010A>T	p.Thr1004Ser	missense	Exon 12 of 18	ENSP00000453342.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 44986 Hom.: 0 Cov.: 8

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000190 AC: 37 AN: 194564 Hom.: 2 Cov.: 0 AF XY: 0.000124 AC XY: 13 AN XY: 105248

African (AFR) AF: 0.00 AC: 0 AN: 5598

American (AMR) AF: 0.000306 AC: 3 AN: 9800

Ashkenazi Jewish (ASJ) AF: 0.000416 AC: 2 AN: 4808

East Asian (EAS) AF: 0.0000624 AC: 1 AN: 16024

South Asian (SAS) AF: 0.00 AC: 0 AN: 33184

European-Finnish (FIN) AF: 0.0000567 AC: 1 AN: 17640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 694

European-Non Finnish (NFE) AF: 0.000259 AC: 25 AN: 96656

Other (OTH) AF: 0.000492 AC: 5 AN: 10160

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 45028 Hom.: 0 Cov.: 8 AF XY: 0.00 AC XY: 0 AN XY: 22086

African (AFR) AF: 0.00 AC: 0 AN: 13652

American (AMR) AF: 0.00 AC: 0 AN: 4750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1120

East Asian (EAS) AF: 0.00 AC: 0 AN: 1470

South Asian (SAS) AF: 0.00 AC: 0 AN: 954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 50

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 19612

Other (OTH) AF: 0.00 AC: 0 AN: 620

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.18
DANN	Benign	0.10
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.57	T
PhyloP100		-0.27
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.76	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.025
MutPred		0.31		Gain of relative solvent accessibility (P = 0.005)
MVP		0.093
MPC		0.18
ClinPred		0.050	T
GERP RS		-1.5
Varity_R		0.017
gMVP		0.039
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: rs34570487; hg19: chr15-89398826;