15-88856926-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001369268.1(ACAN):c.4341G>T(p.Glu1447Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,568,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1447K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

ACAN
NM_001369268.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.07

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

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, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
spondyloepimetaphyseal dysplasia, aggrecan type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
short stature-advanced bone age-early-onset osteoarthritis syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACAN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.040175796).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.0000153

AC:

AN:

131112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000334

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000264

AC:

AN:

1437260

Hom.:

Cov.:

AF XY:

0.0000196

AC XY:

AN XY:

715376

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32484

American (AMR)

AF:

0.00

AC:

AN:

43542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24992

East Asian (EAS)

AF:

0.00

AC:

AN:

38546

South Asian (SAS)

AF:

0.00

AC:

AN:

85242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52766

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5416

European-Non Finnish (NFE)

AF:

0.0000338

AC:

AN:

1095764

Other (OTH)

AF:

0.0000171

AC:

AN:

58508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000153

AC:

AN:

131112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

64586

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

34458

American (AMR)

AF:

0.00

AC:

AN:

13698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3140

East Asian (EAS)

AF:

0.00

AC:

AN:

4148

South Asian (SAS)

AF:

0.00

AC:

AN:

3942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

184

European-Non Finnish (NFE)

AF:

0.0000334

AC:

AN:

59866

Other (OTH)

AF:

0.00

AC:

AN:

1818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.0010

(source)

DANN

Benign

0.22

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0029

LIST_S2

Benign

0.29

T;T;T;T;T;.

M_CAP

Benign

0.079

MetaRNN

Benign

0.040

T;T;T;T;T;T

MetaSVM

Benign

-0.64

PhyloP100

-4.1

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

0.038

GERP RS

-5.3

Varity_R

0.032

gMVP

0.055

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over