NM_002224.4:c.160+48T>C

Variant names:

• chr6-33640602-T-C
• rs4713647
• NM_002224.4:c.160+48T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002224.4(ITPR3):​c.160+48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.988 in 1,503,214 control chromosomes in the GnomAD database, including 733,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.97 (71666 hom., cov: 32)
  • Exomes 𝑓: 0.99 (661565 hom.)
• Consequence: ITPR3 NM_002224.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.713
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 6-33640602-T-C is Benign according to our data. Variant chr6-33640602-T-C is described in ClinVar as [Benign]. Clinvar id is 1220735.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.984 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR3	NM_002224.4	c.160+48T>C		intron_variant	Intron 2 of 57	ENST00000605930.3	NP_002215.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR3	ENST00000605930.3	c.160+48T>C		intron_variant	Intron 2 of 57	1	NM_002224.4	ENSP00000475177.1
ITPR3	ENST00000374316.9	c.160+48T>C		intron_variant	Intron 3 of 58	5		ENSP00000363435.4

Frequencies

GnomAD3 genomes AF: 0.970 AC: 147543 AN: 152140 Hom.: 71613 Cov.: 32

Gnomad AFR AF: 0.920

Gnomad AMI AF: 0.966

Gnomad AMR AF: 0.977

Gnomad ASJ AF: 0.974

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.995

Gnomad FIN AF: 0.998

Gnomad MID AF: 0.911

Gnomad NFE AF: 0.990

Gnomad OTH AF: 0.965

GnomAD2 exomes AF: 0.985 AC: 206201 AN: 209352 AF XY: 0.986

Gnomad AFR exome AF: 0.918

Gnomad AMR exome AF: 0.985

Gnomad ASJ exome AF: 0.979

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.998

Gnomad NFE exome AF: 0.990

Gnomad OTH exome AF: 0.986

GnomAD4 exome AF: 0.990 AC: 1336836 AN: 1350956 Hom.: 661565 Cov.: 19 AF XY: 0.990 AC XY: 665999 AN XY: 673024

African (AFR) AF: 0.919 AC: 28169 AN: 30640

American (AMR) AF: 0.984 AC: 36165 AN: 36758

Ashkenazi Jewish (ASJ) AF: 0.977 AC: 21534 AN: 22046

East Asian (EAS) AF: 0.999 AC: 38728 AN: 38784

South Asian (SAS) AF: 0.989 AC: 75653 AN: 76462

European-Finnish (FIN) AF: 0.997 AC: 51670 AN: 51834

Middle Eastern (MID) AF: 0.953 AC: 5150 AN: 5402

European-Non Finnish (NFE) AF: 0.992 AC: 1024337 AN: 1032778

Other (OTH) AF: 0.985 AC: 55430 AN: 56252

GnomAD4 genome AF: 0.970 AC: 147655 AN: 152258 Hom.: 71666 Cov.: 32 AF XY: 0.972 AC XY: 72340 AN XY: 74438

African (AFR) AF: 0.920 AC: 38196 AN: 41516

American (AMR) AF: 0.977 AC: 14951 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.974 AC: 3382 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5152 AN: 5164

South Asian (SAS) AF: 0.995 AC: 4802 AN: 4828

European-Finnish (FIN) AF: 0.998 AC: 10609 AN: 10628

Middle Eastern (MID) AF: 0.912 AC: 268 AN: 294

European-Non Finnish (NFE) AF: 0.990 AC: 67376 AN: 68030

Other (OTH) AF: 0.965 AC: 2038 AN: 2112

Alfa AF: 0.984 Hom.: 111204

Bravo AF: 0.965

Asia WGS AF: 0.990 AC: 3443 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.7
DANN	Benign	0.69
PhyloP100		-0.71
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: rs4713647; hg19: chr6-33608379;