19-16482507-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_145046.5(CALR3):c.861G>A(p.Thr287=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,614,202 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (15 hom., cov: 33)
  • Exomes 𝑓: 0.015 (197 hom.)
• Consequence: CALR3 NM_145046.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -7.85

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-16482507-C-T is Benign according to our data. Variant chr19-16482507-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 220787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-16482507-C-T is described in Lovd as [Benign]. Variant chr19-16482507-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-7.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0117 (1775/152328) while in subpopulation NFE AF= 0.016 (1091/68034). AF 95% confidence interval is 0.0152. There are 15 homozygotes in gnomad4. There are 951 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1772 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALR3	NM_145046.5	c.861G>A	p.Thr287=	synonymous_variant	7/9	ENST00000269881.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALR3	ENST00000269881.8	c.861G>A	p.Thr287=	synonymous_variant	7/9	1	NM_145046.5	P1
CALR3	ENST00000602234.1	n.535G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1772 AN: 152210 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.0136

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.0122 AC: 3060 AN: 251488 Hom.: 38 AF XY: 0.0123 AC XY: 1674 AN XY: 135918

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00869

Gnomad FIN exome AF: 0.0361

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.0148 AC: 21571 AN: 1461874 Hom.: 197 Cov.: 45 AF XY: 0.0147 AC XY: 10726 AN XY: 727240

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.0104

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00949

Gnomad4 FIN exome AF: 0.0371

Gnomad4 NFE exome AF: 0.0158

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.0117 AC: 1775 AN: 152328 Hom.: 15 Cov.: 33 AF XY: 0.0128 AC XY: 951 AN XY: 74494

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.0136

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00974

Gnomad4 FIN AF: 0.0392

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.0125 Hom.: 5

Bravo AF: 0.00823

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0150

EpiControl AF: 0.0133

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 19 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 17, 2017	Variant summary: The CALR3 c.861G>A (p.Thr287Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. 3/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may not abrogate existing or create new ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1523/121410 control chromosomes (18 homozygotes) from ExAC at a frequency of 0.0125443, which is approximately 502 times the estimated maximal expected allele frequency of a pathogenic CALR3 variant (0.000025), suggesting this variant is likely a benign polymorphism. 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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2020	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2013

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
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.052
Dann	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs118131979; hg19: chr19-16593318;