NM_145046.5:c.820G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_145046.5(CALR3):c.820G>A(p.Val274Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,614,166 control chromosomes in the GnomAD database, including 1,058 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 140 hom., cov: 33)

Exomes 𝑓: 0.011 ( 918 hom. )

Consequence

CALR3
NM_145046.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.36

Publications

13 publications found

Variant links:

COSMIC-nc: COSV107207096

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030251443).

BP6

Variant 19-16482548-C-T is Benign according to our data. Variant chr19-16482548-C-T is described in ClinVar as [Benign]. Clinvar id is 192183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALR3	NM_145046.5 link	c.820G>A	p.Val274Ile	missense_variant	Exon 7 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.820G>A	p.Val274Ile	missense_variant	Exon 7 of 9	1	NM_145046.5	ENSP00000269881.3	Q96L12
ENSG00000141979	ENST00000409035.1 link	n.*623G>A		non_coding_transcript_exon_variant	Exon 10 of 12	2		ENSP00000386951.2	B8ZZF3
ENSG00000141979	ENST00000409035.1 link	n.*623G>A		3_prime_UTR_variant	Exon 10 of 12	2		ENSP00000386951.2	B8ZZF3
CALR3	ENST00000602234.1 link	n.494G>A		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0267

AC:

4065

AN:

152168

Hom.:

136

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0528

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0835

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.0302

Gnomad SAS

AF:

0.00725

Gnomad FIN

AF:

0.00377

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00429

Gnomad OTH

AF:

0.0272

GnomAD2 exomes

AF:

0.0347

AC:

8722

AN:

251488

AF XY:

0.0264

show subpopulations

Gnomad AFR exome

AF:

0.0514

Gnomad AMR exome

AF:

0.189

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.0246

Gnomad FIN exome

AF:

0.00365

Gnomad NFE exome

AF:

0.00429

Gnomad OTH exome

AF:

0.0248

GnomAD4 exome

AF:

0.0110

AC:

16047

AN:

1461880

Hom.:

918

Cov.:

AF XY:

0.00986

AC XY:

7174

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0534

AC:

1789

AN:

33478

American (AMR)

AF:

0.175

AC:

7808

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00425

AC:

111

AN:

26136

East Asian (EAS)

AF:

0.0237

AC:

941

AN:

39700

South Asian (SAS)

AF:

0.00512

AC:

442

AN:

86258

European-Finnish (FIN)

AF:

0.00399

AC:

213

AN:

53418

Middle Eastern (MID)

AF:

0.00971

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00351

AC:

3908

AN:

1112006

Other (OTH)

AF:

0.0129

AC:

779

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

995

1990

2984

3979

4974

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

288

576

864

1152

1440

<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:

0.0269

AC:

4089

AN:

152286

Hom.:

140

Cov.:

AF XY:

0.0274

AC XY:

2041

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0530

AC:

2201

AN:

41564

American (AMR)

AF:

0.0842

AC:

1288

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3470

East Asian (EAS)

AF:

0.0305

AC:

158

AN:

5182

South Asian (SAS)

AF:

0.00684

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00377

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00429

AC:

292

AN:

68016

Other (OTH)

AF:

0.0269

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

202

404

606

808

1010

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0128

Hom.:

265

Bravo

AF:

0.0368

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.0497

AC:

219

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.0301

AC:

3657

Asia WGS

AF:

0.0280

AC:

AN:

3478

EpiCase

AF:

0.00338

EpiControl

AF:

0.00362

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Hypertrophic cardiomyopathy 19

Benign:3

Oct 03, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 21, 2015

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Aug 17, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The CALR3 c.820G>A (p.Val274Ile) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict benign outcome for this variant. This variant was found in 3671/123152 control chromosomes (320 homozygotes) from ExAC and literature, predominantly observed in the Latino subpopulation at a frequency of 0.214458 (2483/11578). This frequency is about 8578 times the estimated maximal expected allele frequency of a pathogenic CALR3 variant (0.000025), thus this is a common benign polymorphism found primarily in the populations of Latino origin. In addition, multiple clinical diagnostic laboratories/reputable databases in ClinVar have classified this variant as benign. To our knowledge, this variant has not been reported in affected individuals in literature. Taken together, this variant is classified as benign. -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cardiovascular phenotype

Benign:1

Oct 03, 2012

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.019

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.070

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0030

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.52

PhyloP100

-1.4

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.87

REVEL

Benign

0.035

Sift

Benign

0.23

Sift4G

Benign

0.23

Polyphen

0.0090

Vest4

0.029

MPC

0.12

ClinPred

0.00074

GERP RS

-3.0

Varity_R

0.024

gMVP

0.082

Mutation Taster

=99/1

polymorphism (auto)

(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

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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