rs938609

Variant names:

• chr15-88855400-T-A
• rs938609
• NM_001369268.1:c.2815T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369268.1(ACAN):​c.2815T>A​(p.Ser939Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 1,613,116 control chromosomes in the GnomAD database, including 291,559 homozygotes. 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 0.52 (21853 hom., cov: 33)
  • Exomes 𝑓: 0.60 (269706 hom.)
• Consequence: ACAN NM_001369268.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.123
• Publications: 33 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.623954E-6).
• BP6: Variant 15-88855400-T-A is Benign according to our data. Variant chr15-88855400-T-A is described in ClinVar as Benign. ClinVar VariationId is 1174760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

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.2815T>A	p.Ser939Thr	missense	Exon 12 of 19	NP_001356197.1	P16112-4
	ACAN	NM_001411097.1		c.2815T>A	p.Ser939Thr	missense	Exon 12 of 18	NP_001398026.1	A0A5K1VW97
	ACAN	NM_013227.4		c.2815T>A	p.Ser939Thr	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.2815T>A	p.Ser939Thr	missense	Exon 12 of 19	ENSP00000453581.2	P16112-4
	ACAN	ENST00000439576.7	TSL:5	c.2815T>A	p.Ser939Thr	missense	Exon 12 of 18	ENSP00000387356.2	P16112-1
	ACAN	ENST00000561243.7	TSL:5	c.2815T>A	p.Ser939Thr	missense	Exon 12 of 18	ENSP00000453342.3	A0A5K1VW97

Frequencies

GnomAD3 genomes AF: 0.520 AC: 78961 AN: 151748 Hom.: 21858 Cov.: 33

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.657

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.595

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.547

GnomAD2 exomes AF: 0.508 AC: 126518 AN: 248810 AF XY: 0.518

Gnomad AFR exome AF: 0.365

Gnomad AMR exome AF: 0.314

Gnomad ASJ exome AF: 0.604

Gnomad EAS exome AF: 0.183

Gnomad FIN exome AF: 0.588

Gnomad NFE exome AF: 0.642

Gnomad OTH exome AF: 0.555

GnomAD4 exome AF: 0.597 AC: 871672 AN: 1461250 Hom.: 269706 Cov.: 91 AF XY: 0.593 AC XY: 431103 AN XY: 726884

African (AFR) AF: 0.366 AC: 12239 AN: 33472

American (AMR) AF: 0.329 AC: 14692 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 15733 AN: 26124

East Asian (EAS) AF: 0.192 AC: 7622 AN: 39696

South Asian (SAS) AF: 0.404 AC: 34875 AN: 86238

European-Finnish (FIN) AF: 0.586 AC: 31195 AN: 53198

Middle Eastern (MID) AF: 0.582 AC: 3353 AN: 5764

European-Non Finnish (NFE) AF: 0.646 AC: 717866 AN: 1111690

Other (OTH) AF: 0.565 AC: 34097 AN: 60360

GnomAD4 genome AF: 0.520 AC: 78961 AN: 151866 Hom.: 21853 Cov.: 33 AF XY: 0.511 AC XY: 37924 AN XY: 74212

African (AFR) AF: 0.372 AC: 15407 AN: 41446

American (AMR) AF: 0.441 AC: 6746 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 2060 AN: 3462

East Asian (EAS) AF: 0.195 AC: 1007 AN: 5172

South Asian (SAS) AF: 0.402 AC: 1933 AN: 4808

European-Finnish (FIN) AF: 0.595 AC: 6259 AN: 10526

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.643 AC: 43634 AN: 67858

Other (OTH) AF: 0.547 AC: 1154 AN: 2110

Alfa AF: 0.606 Hom.: 9228

Bravo AF: 0.502

TwinsUK AF: 0.664 AC: 2462

ALSPAC AF: 0.654 AC: 2519

ESP6500AA AF: 0.392 AC: 1491

ESP6500EA AF: 0.648 AC: 5335

ExAC AF: 0.517 AC: 62405

Asia WGS AF: 0.337 AC: 1173 AN: 3478

EpiCase AF: 0.638

EpiControl AF: 0.640

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Osteochondritis dissecans (1)
-	-	1	Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (1)
-	-	1	Spondyloepimetaphyseal dysplasia, aggrecan type (1)
-	-	1	Spondyloepiphyseal dysplasia, Kimberley type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.1
DANN	Uncertain	0.99
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0000086	T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.12
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.23
Sift	Benign	0.14	T
Sift4G	Uncertain	0.025	D
Vest4		0.054
MPC		0.27
ClinPred		0.0044	T
GERP RS		1.2
Varity_R		0.096
gMVP		0.24
Mutation Taster		=98/2	polymorphism (auto)

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: rs938609; hg19: chr15-89398631; COSMIC: COSV61357843; COSMIC: COSV61357843;