chr15-88813601-G-T

Variant names:

• chr15-88813601-G-T
• rs11633371
• NM_001369268.1:c.-8+9792G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001369268.1(ACAN):​c.-8+9792G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 152,012 control chromosomes in the GnomAD database, including 22,496 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (22496 hom., cov: 32)
• Consequence: ACAN NM_001369268.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.324
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.883 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.-8+9792G>T		intron	N/A	NP_001356197.1	P16112-4
	ACAN	NM_001411097.1		c.-8+9792G>T		intron	N/A	NP_001398026.1	A0A5K1VW97
	ACAN	NM_013227.4		c.-8+9792G>T		intron	N/A	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.-8+9792G>T		intron	N/A	ENSP00000453581.2	P16112-4
	ACAN	ENST00000558207.5	TSL:1	c.-8+9792G>T		intron	N/A	ENSP00000453003.1	Q6PID9
	ACAN	ENST00000439576.7	TSL:5	c.-8+9792G>T		intron	N/A	ENSP00000387356.2	P16112-1

Frequencies

GnomAD3 genomes AF: 0.536 AC: 81370 AN: 151894 Hom.: 22457 Cov.: 32

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.905

Gnomad SAS AF: 0.530

Gnomad FIN AF: 0.609

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.505

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.536 AC: 81469 AN: 152012 Hom.: 22496 Cov.: 32 AF XY: 0.547 AC XY: 40634 AN XY: 74318

African (AFR) AF: 0.570 AC: 23636 AN: 41442

American (AMR) AF: 0.581 AC: 8880 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1371 AN: 3470

East Asian (EAS) AF: 0.904 AC: 4676 AN: 5170

South Asian (SAS) AF: 0.529 AC: 2554 AN: 4824

European-Finnish (FIN) AF: 0.609 AC: 6427 AN: 10556

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32284 AN: 67954

Other (OTH) AF: 0.507 AC: 1070 AN: 2110

Alfa AF: 0.494 Hom.: 80185

Bravo AF: 0.539

Asia WGS AF: 0.680 AC: 2365 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.19
DANN	Benign	0.55
PhyloP100		-0.32
Mutation Taster		=100/0	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: rs11633371; hg19: chr15-89356832;