rs143932873

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1PP3_ModerateBS2

The NM_145046.5(CALR3):c.403G>A(p.Asp135Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000255 in 1,598,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D135G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

CALR3
NM_145046.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:5

Conservation

PhyloP100: 5.47

Publications

4 publications found

Variant links:

Genes affected

CALR3 (HGNC:20407): (calreticulin 3) The protein encoded by this gene belongs to the calreticulin family, members of which are calcium-binding chaperones localized mainly in the endoplasmic reticulum. This protein is also localized to the endoplasmic reticulum lumen, however, its capacity for calcium-binding may be absent or much lower than other family members. This gene is specifically expressed in the testis, and may be required for sperm fertility. Mutation in this gene has been associated with familial hypertrophic cardiomyopathy. [provided by RefSeq, Dec 2011]

CALR3 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CALR3 links:

ENSG00000141979 (HGNC:):

ENSG00000141979 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity CALR3_HUMAN

PP3

MetaRNN computational evidence supports a deleterious effect, 0.921

BS2

High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALR3	NM_145046.5 link	c.403G>A	p.Asp135Asn	missense_variant	Exon 4 of 9	ENST00000269881.8	NP_659483.2	Q96L12A0A140VJF7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CALR3	ENST00000269881.8 link	c.403G>A	p.Asp135Asn	missense_variant	Exon 4 of 9	1	NM_145046.5	ENSP00000269881.3	Q96L12
ENSG00000141979	ENST00000409035.1 link	n.*482-2467G>A		intron_variant	Intron 8 of 11	2		ENSP00000386951.2	B8ZZF3
CALR3	ENST00000600762.1 link	c.187G>A	p.Asp63Asn	missense_variant	Exon 3 of 4	3		ENSP00000471533.1	M0R0Y8

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

151952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000762

AC:

AN:

249342

AF XY:

0.0000668

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000270

AC:

390

AN:

1446406

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

184

AN XY:

720366

show subpopulations

African (AFR)

AF:

0.0000906

AC:

AN:

33110

American (AMR)

AF:

0.00

AC:

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25994

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39606

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85830

European-Finnish (FIN)

AF:

0.0000376

AC:

AN:

53256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.000346

AC:

380

AN:

1098404

Other (OTH)

AF:

0.0000501

AC:

AN:

59834

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.419

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000112

AC:

AN:

151952

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74190

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41358

American (AMR)

AF:

0.00

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000147

Hom.:

Bravo

AF:

0.000132

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy 19

Uncertain:1

Sep 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 135 of the CALR3 protein (p.Asp135Asn). This variant is present in population databases (rs143932873, gnomAD 0.02%). This missense change has been observed in individual(s) with cardiomyopathy (PMID: 25163546, 29988065, 30847666). ClinVar contains an entry for this variant (Variation ID: 410619). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CALR3 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.061

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.42

MutationAssessor

Pathogenic

3.6

PhyloP100

5.5

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.89

MVP

0.90

MPC

0.63

ClinPred

0.98

GERP RS

5.8

Varity_R

0.63

gMVP

0.87

Mutation Taster

=32/68

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.25

Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over