rs3784757

Variant names:

• chr15-88860173-G-A
• rs3784757
• NM_001369268.1:c.6833-153G>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.6833-153G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 150,454 control chromosomes in the GnomAD database, including 2,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.13 (2578 hom., cov: 29)
• Consequence: ACAN NM_001369268.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0650
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 15-88860173-G-A is Benign according to our data. Variant chr15-88860173-G-A is described in ClinVar as Benign. ClinVar VariationId is 1242446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAN	NM_001369268.1	c.6833-153G>A		intron_variant	Intron 12 of 18	ENST00000560601.4	NP_001356197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAN	ENST00000560601.4	c.6833-153G>A		intron_variant	Intron 12 of 18	3	NM_001369268.1	ENSP00000453581.2

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19377 AN: 150346 Hom.: 2558 Cov.: 29

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.0941

Gnomad ASJ AF: 0.0546

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.0657

Gnomad FIN AF: 0.0341

Gnomad MID AF: 0.106

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.109

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

GnomAD4 genome AF: 0.129 AC: 19437 AN: 150454 Hom.: 2578 Cov.: 29 AF XY: 0.128 AC XY: 9400 AN XY: 73452

African (AFR) AF: 0.343 AC: 13871 AN: 40434

American (AMR) AF: 0.0947 AC: 1435 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.0546 AC: 189 AN: 3462

East Asian (EAS) AF: 0.125 AC: 637 AN: 5114

South Asian (SAS) AF: 0.0641 AC: 303 AN: 4724

European-Finnish (FIN) AF: 0.0341 AC: 355 AN: 10424

Middle Eastern (MID) AF: 0.0972 AC: 28 AN: 288

European-Non Finnish (NFE) AF: 0.0347 AC: 2352 AN: 67846

Other (OTH) AF: 0.110 AC: 230 AN: 2096

Alfa AF: 0.0680 Hom.: 1101

Bravo AF: 0.148

Asia WGS AF: 0.103 AC: 360 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.5
DANN	Benign	0.79
PhyloP100		-0.065
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3784757; hg19: chr15-89403404; COSMIC: COSV61357583;