rs938610

Variant names:

• chr15-88836064-G-A
• rs938610
• NM_001369268.1:c.-7-136G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-88836064-G-A
• chr15-88836064-G-T

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.-7-136G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.593 in 631,010 control chromosomes in the GnomAD database, including 114,815 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.58 (26198 hom., cov: 32)
  • Exomes 𝑓: 0.60 (88617 hom.)
• Consequence: ACAN NM_001369268.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.51
• Publications: 3 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: 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, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• spondyloepimetaphyseal dysplasia, aggrecan type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 15-88836064-G-A is Benign according to our data. Variant chr15-88836064-G-A is described in ClinVar as Benign. ClinVar VariationId is 1250552.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.637 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.-7-136G>A		intron	N/A	NP_001356197.1	P16112-4
	ACAN	NM_001411097.1		c.-7-136G>A		intron	N/A	NP_001398026.1	A0A5K1VW97
	ACAN	NM_013227.4		c.-7-136G>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.-7-136G>A		intron	N/A	ENSP00000453581.2	P16112-4
	ACAN	ENST00000558207.5	TSL:1	c.-7-136G>A		intron	N/A	ENSP00000453003.1	Q6PID9
	ACAN	ENST00000439576.7	TSL:5	c.-7-136G>A		intron	N/A	ENSP00000387356.2	P16112-1

Frequencies

GnomAD3 genomes AF: 0.579 AC: 88019 AN: 151914 Hom.: 26191 Cov.: 32

Gnomad AFR AF: 0.503

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.674

Gnomad MID AF: 0.701

Gnomad NFE AF: 0.642

Gnomad OTH AF: 0.611

GnomAD4 exome AF: 0.597 AC: 286155 AN: 478978 Hom.: 88617 AF XY: 0.594 AC XY: 148630 AN XY: 250318

African (AFR) AF: 0.512 AC: 6610 AN: 12904

American (AMR) AF: 0.548 AC: 11187 AN: 20410

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 8746 AN: 14294

East Asian (EAS) AF: 0.233 AC: 7191 AN: 30846

South Asian (SAS) AF: 0.499 AC: 21254 AN: 42620

European-Finnish (FIN) AF: 0.659 AC: 27574 AN: 41864

Middle Eastern (MID) AF: 0.695 AC: 1409 AN: 2028

European-Non Finnish (NFE) AF: 0.647 AC: 185890 AN: 287302

Other (OTH) AF: 0.610 AC: 16294 AN: 26710

GnomAD4 genome AF: 0.579 AC: 88073 AN: 152032 Hom.: 26198 Cov.: 32 AF XY: 0.578 AC XY: 42926 AN XY: 74322

African (AFR) AF: 0.503 AC: 20831 AN: 41448

American (AMR) AF: 0.574 AC: 8772 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2144 AN: 3470

East Asian (EAS) AF: 0.229 AC: 1179 AN: 5158

South Asian (SAS) AF: 0.486 AC: 2342 AN: 4814

European-Finnish (FIN) AF: 0.674 AC: 7132 AN: 10574

Middle Eastern (MID) AF: 0.709 AC: 207 AN: 292

European-Non Finnish (NFE) AF: 0.642 AC: 43619 AN: 67980

Other (OTH) AF: 0.609 AC: 1284 AN: 2110

Alfa AF: 0.599 Hom.: 4679

Bravo AF: 0.571

Asia WGS AF: 0.418 AC: 1455 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.93
CADD	Benign	0.092
DANN	Benign	0.48
PhyloP100		-1.5
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: rs938610; hg19: chr15-89379295;