rs144370982

Positions:

• chr19-16479283-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000269881.8(CALR3):​c.1012-9T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000578 in 1,613,944 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: CALR3 ENST00000269881.8 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004352
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.72

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 19-16479283-A-G is Benign according to our data. Variant chr19-16479283-A-G is described in ClinVar as [Benign]. Clinvar id is 241948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-16479283-A-G is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 371 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALR3	NM_145046.5	c.1012-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000269881.8	NP_659483.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALR3	ENST00000269881.8	c.1012-9T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_145046.5	ENSP00000269881	P1

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 371 AN: 152038 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00204

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000891 AC: 224 AN: 251362 Hom.: 0 AF XY: 0.000729 AC XY: 99 AN XY: 135878

Gnomad AFR exome AF: 0.00695

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000384 AC: 562 AN: 1461788 Hom.: 1 Cov.: 31 AF XY: 0.000355 AC XY: 258 AN XY: 727216

Gnomad4 AFR exome AF: 0.00633

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00735

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00244 AC: 371 AN: 152156 Hom.: 2 Cov.: 31 AF XY: 0.00257 AC XY: 191 AN XY: 74390

Gnomad4 AFR AF: 0.00722

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.00156 Hom.: 0

Bravo AF: 0.00279

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hypertrophic cardiomyopathy 19 Benign:2

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Aug 16, 2017

Variant summary: The CALR3 c.1012-9T>C variant involves the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a benign 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 109/121320 control chromosomes from ExAC at a frequency of 0.0008985, which is approximately 36 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 via publications. Taken together, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	15
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000044
dbscSNV1_RF	Benign	0.016
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

LitVar

Other links and lift over

dbSNP: rs144370982; hg19: chr19-16590094;