Variant rs34570487 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.266

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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 GnomAd4 at 694 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACAN	NM_001369268.1 linkuse as main transcript	c.3010A>G	p.Thr1004Ala	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 linkuse as main transcript	c.3010A>G	p.Thr1004Ala	missense_variant	12/19	3	NM_001369268.1	ENSP00000453581	P1

Frequencies

GnomAD3 genomes

AF:

0.0155

AC:

690

AN:

44496

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.0627

AC XY:

5601

AN XY:

89356

show subpopulations

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.:

Cov.:

AF XY:

0.0151

AC XY:

330

AN XY:

21878

show subpopulations

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.:

ExAC

AF:

0.00484

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 01, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.12

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

LIST_S2

Benign

0.57

T;T;T;T;T;.

MetaRNN

Benign

0.0023

T;T;T;T;T;T

MetaSVM

Benign

-0.36

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.71

.;N;.;N;N;N

REVEL

Benign

0.25

Sift

Uncertain

0.016

.;D;.;D;D;D

Sift4G

Benign

0.65

.;T;T;T;T;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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over