rs34570487

chr15-88855595-A-Gchr15-88855595-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001369268.1(ACAN):c.3010A>G(p.Thr1004Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (3 hom., cov: 8)
  • Exomes 𝑓: 0.068 (54 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACAN NM_001369268.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.266

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023103654).
• BP6: Variant 15-88855595-A-G is Benign according to our data. Variant chr15-88855595-A-G is described in ClinVar as [Benign]. Clinvar id is 445330.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-88855595-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0156 (694/44530) while in subpopulation EAS AF= 0.0416 (60/1442). AF 95% confidence interval is 0.0332. There are 3 homozygotes in gnomad4. There are 330 alleles in male gnomad4 subpopulation. Median coverage is 8. This position pass quality control queck.
• BS2: High AC in GnomAd at 690 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAN	NM_001369268.1	c.3010A>G	p.Thr1004Ala	missense_variant	12/19	ENST00000560601.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAN	ENST00000560601.4	c.3010A>G	p.Thr1004Ala	missense_variant	12/19	3	NM_001369268.1	P1

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 690 AN: 44496 Hom.: 3 Cov.: 8

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.0333

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0108

Gnomad EAS AF: 0.0416

Gnomad SAS AF: 0.0189

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.0962

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.0132

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0685 AC: 11200 AN: 163578 Hom.: 54 Cov.: 0 AF XY: 0.0627 AC XY: 5601 AN XY: 89356

Gnomad4 AFR exome AF: 0.0610

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.107

Gnomad4 EAS exome AF: 0.137

Gnomad4 SAS exome AF: 0.0158

Gnomad4 FIN exome AF: 0.0239

Gnomad4 NFE exome AF: 0.0787

Gnomad4 OTH exome AF: 0.0869

GnomAD4 genome AF: 0.0156 AC: 694 AN: 44530 Hom.: 3 Cov.: 8 AF XY: 0.0151 AC XY: 330 AN XY: 21878

Gnomad4 AFR AF: 0.0187

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.0108

Gnomad4 EAS AF: 0.0416

Gnomad4 SAS AF: 0.0210

Gnomad4 FIN AF: 0.0140

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.0131

Alfa AF: 0.101 Hom.: 0

ExAC AF: 0.00484 AC: 62

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Aug 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	8.0
Dann	Benign	0.43
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.57	T;T;T;T;T;.
MetaRNN	Benign	0.0023	T;T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.68	T
Vest4		0.082, 0.073, 0.083, 0.069, 0.077
MutPred		0.31		Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);.;Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);
MPC		0.23
ClinPred		0.0037	T
GERP RS		-1.5
Varity_R		0.043
gMVP		0.062

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: rs34570487; hg19: chr15-89398826; COSMIC: COSV61363796; COSMIC: COSV61363796;