NM_001369268.1:c.71-187G>A

Variant names:

• chr15-88838476-G-A
• rs115252131
• NM_001369268.1:c.71-187G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001369268.1(ACAN):​c.71-187G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 152,256 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.040 (213 hom., cov: 32)
• Consequence: ACAN NM_001369268.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0580
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 15-88838476-G-A is Benign according to our data. Variant chr15-88838476-G-A is described in ClinVar as Benign. ClinVar VariationId is 1261820.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0862 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.71-187G>A		intron	N/A	NP_001356197.1	P16112-4
	ACAN	NM_001411097.1		c.71-187G>A		intron	N/A	NP_001398026.1	A0A5K1VW97
	ACAN	NM_013227.4		c.71-187G>A		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.71-187G>A		intron	N/A	ENSP00000453581.2	P16112-4
	ACAN	ENST00000558207.5	TSL:1	c.71-187G>A		intron	N/A	ENSP00000453003.1	Q6PID9
	ACAN	ENST00000439576.7	TSL:5	c.71-187G>A		intron	N/A	ENSP00000387356.2	P16112-1

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6021 AN: 152138 Hom.: 210 Cov.: 32

Gnomad AFR AF: 0.0884

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0316

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.00598

Gnomad SAS AF: 0.0912

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0454

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

GnomAD4 genome AF: 0.0396 AC: 6026 AN: 152256 Hom.: 213 Cov.: 32 AF XY: 0.0404 AC XY: 3010 AN XY: 74446

African (AFR) AF: 0.0886 AC: 3680 AN: 41536

American (AMR) AF: 0.0315 AC: 483 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 153 AN: 3472

East Asian (EAS) AF: 0.00599 AC: 31 AN: 5176

South Asian (SAS) AF: 0.0896 AC: 431 AN: 4812

European-Finnish (FIN) AF: 0.0101 AC: 107 AN: 10610

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0148 AC: 1009 AN: 68020

Other (OTH) AF: 0.0449 AC: 95 AN: 2114

Alfa AF: 0.00493 Hom.: 7

Bravo AF: 0.0424

Asia WGS AF: 0.0670 AC: 232 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.65
PhyloP100		-0.058
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: rs115252131; hg19: chr15-89381707;