rs376479901

Variant names:

• chr19-16485263-A-G
• rs376479901
• NM_145046.5:c.398-6T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Publications: 0 publications found

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

ENSG00000141979 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 220700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 172 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145046.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALR3	NM_145046.5	MANE Select	c.398-6T>C		splice_region intron	N/A	NP_659483.2	A0A140VJF7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALR3	ENST00000269881.8	TSL:1 MANE Select	c.398-6T>C		splice_region intron	N/A	ENSP00000269881.3	Q96L12
	ENSG00000141979	ENST00000409035.1	TSL:2	n.*482-2478T>C		intron	N/A	ENSP00000386951.2	B8ZZF3
	CALR3	ENST00000932464.1		c.398-6T>C		splice_region intron	N/A	ENSP00000602523.1

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152164 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00122 AC: 304 AN: 248536 AF XY: 0.00109

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 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.: 4 Cov.: 25 AF XY: 0.00122 AC XY: 864 AN XY: 706646

African (AFR) AF: 0.0000924 AC: 3 AN: 32484

American (AMR) AF: 0.000337 AC: 15 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.000310 AC: 8 AN: 25774

East Asian (EAS) AF: 0.00 AC: 0 AN: 39432

South Asian (SAS) AF: 0.00 AC: 0 AN: 85134

European-Finnish (FIN) AF: 0.00474 AC: 252 AN: 53190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.00138 AC: 1476 AN: 1069742

Other (OTH) AF: 0.00104 AC: 61 AN: 58852

GnomAD4 genome AF: 0.00113 AC: 172 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.00120 AC XY: 89 AN XY: 74454

African (AFR) AF: 0.000241 AC: 10 AN: 41562

American (AMR) AF: 0.000196 AC: 3 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00499 AC: 53 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00150 AC: 102 AN: 68024

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.000748

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hypertrophic cardiomyopathy 19 (4)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.2
DANN	Benign	0.50
PhyloP100		2.4
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs376479901; hg19: chr19-16596074;