NM_145046.5:c.398-6T>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_145046.5(CALR3):c.398-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,567,112 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 4 hom. )

Consequence

CALR3
NM_145046.5 splice_region, intron

Scores

Splicing: ADA: 0.00008256

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.37

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 links:

ENSG00000141979 (HGNC:):

ENSG00000141979 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 19-16485263-A-G is Benign according to our data. Variant chr19-16485263-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 220700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-16485263-A-G is described in Lovd as [Likely_benign]. Variant chr19-16485263-A-G is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 172 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALR3	NM_145046.5 link	c.398-6T>C		splice_region_variant, intron_variant	Intron 3 of 8	ENST00000269881.8	NP_659483.2	Q96L12A0A140VJF7

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CALR3	ENST00000269881.8 link	c.398-6T>C	splice_region_variant, intron_variant	Intron 3 of 8	1	NM_145046.5	ENSP00000269881.3	Q96L12
ENSG00000141979	ENST00000409035.1 link	n.*482-2478T>C	intron_variant	Intron 8 of 11	2		ENSP00000386951.2	B8ZZF3
CALR3	ENST00000600762.1 link	c.182-6T>C	splice_region_variant, intron_variant	Intron 2 of 3	3		ENSP00000471533.1	M0R0Y8

Frequencies

GnomAD3 genomes

AF:

0.00113

AC:

172

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00499

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00150

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00122

AC:

304

AN:

248536

Hom.:

AF XY:

0.00109

AC XY:

147

AN XY:

134358

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.000403

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00542

Gnomad NFE exome

AF:

0.00145

Gnomad OTH exome

AF:

0.00148

GnomAD4 exome

AF:

0.00128

AC:

1815

AN:

1414830

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

864

AN XY:

706646

show subpopulations

Gnomad4 AFR exome

AF:

0.0000924

Gnomad4 AMR exome

AF:

0.000337

Gnomad4 ASJ exome

AF:

0.000310

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00474

Gnomad4 NFE exome

AF:

0.00138

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.00113

AC:

172

AN:

152282

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00499

Gnomad4 NFE

AF:

0.00150

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.000748

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 19

Benign:4

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:1

Aug 23, 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.398-6T>C variant involves the alteration of a non-conserved intronic nucleotide. Mutation Taster predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 137/105290 control chromosomes from ExAC at a frequency of 0.0013012, which is approximately 52 times the estimated maximal expected allele frequency of a pathogenic CALR3 variant (0.000025), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory in ClinVar has 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

6.2

DANN

Benign

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000083

dbscSNV1_RF

Benign

0.0040

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.20

Position offset: -6

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