rs3743398

Positions:

• chr15-88855176-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369268.1(ACAN):​c.2591C>T​(p.Pro864Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,607,782 control chromosomes in the GnomAD database, including 28,870 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2112 hom., cov: 34)
  • Exomes 𝑓: 0.18 (26758 hom.)
• Consequence: ACAN NM_001369268.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.918

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013746023).
• BP6: Variant 15-88855176-C-T is Benign according to our data. Variant chr15-88855176-C-T is described in ClinVar as [Benign]. Clinvar id is 1229794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-88855176-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACAN	NM_001369268.1	c.2591C>T	p.Pro864Leu	missense_variant	12/19	ENST00000560601.4	NP_001356197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACAN	ENST00000560601.4	c.2591C>T	p.Pro864Leu	missense_variant	12/19	3	NM_001369268.1	ENSP00000453581.2

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22571 AN: 152174 Hom.: 2111 Cov.: 34

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0364

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.164

GnomAD3 exomes AF: 0.153 AC: 37481 AN: 245408 Hom.: 3526 AF XY: 0.152 AC XY: 20160 AN XY: 133048

Gnomad AFR exome AF: 0.0362

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.102

Gnomad SAS exome AF: 0.0360

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.184 AC: 267560 AN: 1455490 Hom.: 26758 Cov.: 82 AF XY: 0.180 AC XY: 130183 AN XY: 723022

Gnomad4 AFR exome AF: 0.0342

Gnomad4 AMR exome AF: 0.106

Gnomad4 ASJ exome AF: 0.182

Gnomad4 EAS exome AF: 0.107

Gnomad4 SAS exome AF: 0.0383

Gnomad4 FIN exome AF: 0.217

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.148 AC: 22564 AN: 152292 Hom.: 2112 Cov.: 34 AF XY: 0.147 AC XY: 10922 AN XY: 74452

Gnomad4 AFR AF: 0.0425

Gnomad4 AMR AF: 0.144

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.105

Gnomad4 SAS AF: 0.0362

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.162

Alfa AF: 0.189 Hom.: 5695

Bravo AF: 0.137

TwinsUK AF: 0.215 AC: 798

ALSPAC AF: 0.206 AC: 794

ESP6500AA AF: 0.0346 AC: 138

ESP6500EA AF: 0.201 AC: 1673

ExAC AF: 0.151 AC: 18291

Asia WGS AF: 0.0540 AC: 188 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Spondyloepimetaphyseal dysplasia, aggrecan type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Spondyloepiphyseal dysplasia, Kimberley type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Uncertain	1.0
Eigen	Benign	0.029
Eigen_PC	Benign	0.0040
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.72	T;T;T;T;T;.
MetaRNN	Benign	0.0014	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.4	.;D;.;D;D;D
REVEL	Benign	0.10
Sift	Benign	0.068	.;T;.;T;T;T
Sift4G	Uncertain	0.015	.;D;D;D;D;D
Vest4		0.058, 0.096, 0.072, 0.11, 0.042
MPC		0.78
ClinPred		0.056	T
GERP RS		4.9
Varity_R		0.11
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs3743398; hg19: chr15-89398407; COSMIC: COSV61357166; COSMIC: COSV61357166;