dbSNP rs34570487: ACAN:p.Thr1004Pro (chr15-88855595-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001369268.1(ACAN):c.3010A>C(p.Thr1004Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T1004A) has been classified as Benign.

Frequency

Genomes: not found (cov: 8)

Exomes 𝑓: 0.00012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACAN
NM_001369268.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.266

Publications

0 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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10686171).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAN	NM_001369268.1 link	c.3010A>C	p.Thr1004Pro	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.3010A>C	p.Thr1004Pro	missense_variant	Exon 12 of 19	3	NM_001369268.1	ENSP00000453581.2		H0YMF1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000123

AC:

AN:

194586

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

105262

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

5598

American (AMR)

AF:

0.00

AC:

AN:

9802

Ashkenazi Jewish (ASJ)

AF:

0.000208

AC:

AN:

4808

East Asian (EAS)

AF:

0.0000624

AC:

AN:

16022

South Asian (SAS)

AF:

0.00

AC:

AN:

33184

European-Finnish (FIN)

AF:

0.000227

AC:

AN:

17636

Middle Eastern (MID)

AF:

0.00

AC:

AN:

694

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

96676

Other (OTH)

AF:

0.0000984

AC:

AN:

10166

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000247728), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.344

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.71

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0071

LIST_S2

Benign

0.41

T;T;T;T;T;.

M_CAP

Benign

0.047

MetaRNN

Benign

0.11

T;T;T;T;T;T

MetaSVM

Uncertain

0.053

PhyloP100

-0.27

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.0

.;N;.;N;N;N

REVEL

Benign

0.21

Sift

Uncertain

0.0060

.;D;.;D;D;D

Sift4G

Benign

0.25

.;T;T;T;T;T

Vest4

0.058, 0.10, 0.068, 0.054, 0.059

MutPred

0.32

Loss of glycosylation at T1004 (P = 0.0247);Loss of glycosylation at T1004 (P = 0.0247);.;Loss of glycosylation at T1004 (P = 0.0247);Loss of glycosylation at T1004 (P = 0.0247);Loss of glycosylation at T1004 (P = 0.0247);

MVP

0.12

MPC

0.26

ClinPred

0.20

GERP RS

-1.5

Varity_R

0.10

gMVP

0.053

Mutation Taster

=98/2

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