15-88855595-A-G

Variant names:

• chr15-88855595-A-G
• rs34570487
• NM_001369268.1:c.3010A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001369268.1(ACAN):​c.3010A>G​(p.Thr1004Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (3 hom., cov: 8)
  • Exomes 𝑓: 0.068 (54 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACAN NM_001369268.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023103654).
• BP6: Variant 15-88855595-A-G is Benign according to our data. Variant chr15-88855595-A-G is described in ClinVar as Benign. ClinVar VariationId is 445330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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>G	p.Thr1004Ala	missense	Exon 12 of 19	NP_001356197.1
	ACAN	NM_001411097.1		c.3010A>G	p.Thr1004Ala	missense	Exon 12 of 18	NP_001398026.1
	ACAN	NM_013227.4		c.3010A>G	p.Thr1004Ala	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>G	p.Thr1004Ala	missense	Exon 12 of 19	ENSP00000453581.2
	ACAN	ENST00000439576.7	TSL:5	c.3010A>G	p.Thr1004Ala	missense	Exon 12 of 18	ENSP00000387356.2
	ACAN	ENST00000561243.7	TSL:5	c.3010A>G	p.Thr1004Ala	missense	Exon 12 of 18	ENSP00000453342.3

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 690 AN: 44496 Hom.: 3 Cov.: 8

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.0333

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0108

Gnomad EAS AF: 0.0416

Gnomad SAS AF: 0.0189

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.0962

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.0132

GnomAD2 exomes AF: 0.0915 AC: 1726 AN: 18870 AF XY: 0.103

Gnomad AFR exome AF: 0.0382

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.0471

Gnomad EAS exome AF: 0.149

Gnomad FIN exome AF: 0.00512

Gnomad NFE exome AF: 0.0577

Gnomad OTH exome AF: 0.117

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0685 AC: 11200 AN: 163578 Hom.: 54 Cov.: 0 AF XY: 0.0627 AC XY: 5601 AN XY: 89356

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

African (AFR) AF: 0.0610 AC: 304 AN: 4986

American (AMR) AF: 0.146 AC: 1034 AN: 7102

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 408 AN: 3826

East Asian (EAS) AF: 0.137 AC: 1475 AN: 10764

South Asian (SAS) AF: 0.0158 AC: 496 AN: 31376

European-Finnish (FIN) AF: 0.0239 AC: 390 AN: 16336

Middle Eastern (MID) AF: 0.0819 AC: 47 AN: 574

European-Non Finnish (NFE) AF: 0.0787 AC: 6323 AN: 80296

Other (OTH) AF: 0.0869 AC: 723 AN: 8318

⚠️ 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 AF: 0.0156 AC: 694 AN: 44530 Hom.: 3 Cov.: 8 AF XY: 0.0151 AC XY: 330 AN XY: 21878

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

African (AFR) AF: 0.0187 AC: 252 AN: 13502

American (AMR) AF: 0.0157 AC: 74 AN: 4700

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 12 AN: 1110

East Asian (EAS) AF: 0.0416 AC: 60 AN: 1442

South Asian (SAS) AF: 0.0210 AC: 20 AN: 952

European-Finnish (FIN) AF: 0.0140 AC: 36 AN: 2572

Middle Eastern (MID) AF: 0.0833 AC: 4 AN: 48

European-Non Finnish (NFE) AF: 0.0114 AC: 222 AN: 19412

Other (OTH) AF: 0.0131 AC: 8 AN: 612

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.101 Hom.: 0

ExAC AF: 0.00484 AC: 62

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 01, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.0
DANN	Benign	0.43
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.36	T
PhyloP100		-0.27
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.25
Sift	Uncertain	0.016	D
Sift4G	Benign	0.65	T
Vest4		0.082
MutPred		0.31		Gain of relative solvent accessibility (P = 0.005)
MPC		0.23
ClinPred		0.0037	T
GERP RS		-1.5
Varity_R		0.043
gMVP		0.062
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; COSMIC: COSV61363796; COSMIC: COSV61363796;