6-33680451-C-T

Variant names:

• chr6-33680451-C-T
• rs2229638
• NM_002224.4:c.4347C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_002224.4(ITPR3):​c.4347C>T​(p.Ala1449Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.899 in 1,613,004 control chromosomes in the GnomAD database, including 651,893 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.90 (61580 hom., cov: 35)
  • Exomes 𝑓: 0.90 (590313 hom.)
• Consequence: ITPR3 NM_002224.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580
• Publications: 22 publications found

Genes affected

ITPR3 (HGNC:6182): (inositol 1,4,5-trisphosphate receptor type 3) This gene encodes a receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular calcium. The receptor contains a calcium channel at the C-terminus and the ligand-binding site at the N-terminus. Knockout studies in mice suggest that type 2 and type 3 inositol 1,4,5-trisphosphate receptors play a key role in exocrine secretion underlying energy metabolism and growth. [provided by RefSeq, Aug 2010]

ITPR3 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease, demyelinating, type 1J

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP7: Synonymous conserved (PhyloP=0.058 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.967 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002224.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR3	NM_002224.4	MANE Select	c.4347C>T	p.Ala1449Ala	synonymous	Exon 32 of 58	NP_002215.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR3	ENST00000605930.3	TSL:1 MANE Select	c.4347C>T	p.Ala1449Ala	synonymous	Exon 32 of 58	ENSP00000475177.1
	ITPR3	ENST00000374316.9	TSL:5	c.4347C>T	p.Ala1449Ala	synonymous	Exon 33 of 59	ENSP00000363435.4

Frequencies

GnomAD3 genomes AF: 0.899 AC: 136757 AN: 152188 Hom.: 61540 Cov.: 35

Gnomad AFR AF: 0.856

Gnomad AMI AF: 0.906

Gnomad AMR AF: 0.930

Gnomad ASJ AF: 0.958

Gnomad EAS AF: 0.989

Gnomad SAS AF: 0.922

Gnomad FIN AF: 0.942

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.899

Gnomad OTH AF: 0.903

GnomAD2 exomes AF: 0.919 AC: 229942 AN: 250160 AF XY: 0.919

Gnomad AFR exome AF: 0.851

Gnomad AMR exome AF: 0.949

Gnomad ASJ exome AF: 0.960

Gnomad EAS exome AF: 0.993

Gnomad FIN exome AF: 0.937

Gnomad NFE exome AF: 0.902

Gnomad OTH exome AF: 0.911

GnomAD4 exome AF: 0.899 AC: 1312481 AN: 1460698 Hom.: 590313 Cov.: 80 AF XY: 0.900 AC XY: 653683 AN XY: 726708

African (AFR) AF: 0.856 AC: 28673 AN: 33480

American (AMR) AF: 0.946 AC: 42315 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.958 AC: 25033 AN: 26118

East Asian (EAS) AF: 0.996 AC: 39530 AN: 39700

South Asian (SAS) AF: 0.915 AC: 78941 AN: 86238

European-Finnish (FIN) AF: 0.933 AC: 48838 AN: 52356

Middle Eastern (MID) AF: 0.880 AC: 5073 AN: 5768

European-Non Finnish (NFE) AF: 0.890 AC: 989730 AN: 1111938

Other (OTH) AF: 0.900 AC: 54348 AN: 60382

GnomAD4 genome AF: 0.899 AC: 136854 AN: 152306 Hom.: 61580 Cov.: 35 AF XY: 0.904 AC XY: 67336 AN XY: 74458

African (AFR) AF: 0.855 AC: 35547 AN: 41552

American (AMR) AF: 0.930 AC: 14242 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.958 AC: 3326 AN: 3472

East Asian (EAS) AF: 0.989 AC: 5126 AN: 5182

South Asian (SAS) AF: 0.921 AC: 4444 AN: 4826

European-Finnish (FIN) AF: 0.942 AC: 10009 AN: 10628

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.899 AC: 61165 AN: 68016

Other (OTH) AF: 0.904 AC: 1913 AN: 2116

Alfa AF: 0.903 Hom.: 212819

Bravo AF: 0.896

Asia WGS AF: 0.944 AC: 3283 AN: 3478

EpiCase AF: 0.904

EpiControl AF: 0.903

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	1.2
DANN	Benign	0.55
PhyloP100		0.058
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2229638; hg19: chr6-33648228; COSMIC: COSV65406724;