rs201505307

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001369268.1(ACAN):c.4341G>C(p.Glu1447Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000534 in 131,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000019 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACAN
NM_001369268.1 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -4.07

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=0.005847603).

BP6

Variant 15-88856926-G-C is Benign according to our data. Variant chr15-88856926-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 402334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000534 (70/131048) while in subpopulation AFR AF= 0.00104 (36/34484). AF 95% confidence interval is 0.000774. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAN	NM_001369268.1 link	c.4341G>C	p.Glu1447Asp	missense_variant	Exon 12 of 19	ENST00000560601.4	NP_001356197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAN	ENST00000560601.4 link	c.4341G>C	p.Glu1447Asp	missense_variant	Exon 12 of 19	3	NM_001369268.1	ENSP00000453581.2		H0YMF1

Frequencies

GnomAD3 genomes

AF:

0.000535

AC:

AN:

130954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000438

Gnomad ASJ

AF:

0.000319

Gnomad EAS

AF:

0.000965

Gnomad SAS

AF:

0.00102

Gnomad FIN

AF:

0.000547

Gnomad MID

AF:

0.00543

Gnomad NFE

AF:

0.000217

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000242

AC:

AN:

248098

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134646

show subpopulations

Gnomad AFR exome

AF:

0.0000658

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000558

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000188

AC:

AN:

1437086

Hom.:

Cov.:

AF XY:

0.0000224

AC XY:

AN XY:

715296

show subpopulations

Gnomad4 AFR exome

AF:

0.000154

Gnomad4 AMR exome

AF:

0.0000230

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000519

Gnomad4 SAS exome

AF:

0.0000587

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000100

Gnomad4 OTH exome

AF:

0.0000513

GnomAD4 genome

AF:

0.000534

AC:

AN:

131048

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

64624

show subpopulations

Gnomad4 AFR

AF:

0.00104

Gnomad4 AMR

AF:

0.000438

Gnomad4 ASJ

AF:

0.000319

Gnomad4 EAS

AF:

0.000967

Gnomad4 SAS

AF:

0.00102

Gnomad4 FIN

AF:

0.000547

Gnomad4 NFE

AF:

0.000217

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000959

Hom.:

ExAC

AF:

0.000555

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 0.6% of African chromosomes in ExAC, frequency high for disorder -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.0010

DANN

Benign

0.25

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.29

T;T;T;T;T;.

M_CAP

Benign

0.079

MetaRNN

Benign

0.0058

T;T;T;T;T;T

MetaSVM

Benign

-0.64

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.010

.;N;.;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.54

.;T;.;T;T;T

Sift4G

Benign

0.63

.;T;T;T;T;T

Vest4

0.029, 0.032, 0.036, 0.037, 0.022

MutPred

0.27

Loss of phosphorylation at S1449 (P = 0.3149);Loss of phosphorylation at S1449 (P = 0.3149);.;Loss of phosphorylation at S1449 (P = 0.3149);Loss of phosphorylation at S1449 (P = 0.3149);Loss of phosphorylation at S1449 (P = 0.3149);

MVP

0.14

MPC

0.18

ClinPred

0.023

GERP RS

-5.3

Varity_R

0.032

gMVP

0.055

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