3-4521072-C-A

Variant names:

• chr3-4521072-C-A
• rs370939479
• NM_001378452.1:c.141C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001378452.1(ITPR1):​c.141C>A​(p.Asn47Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N47S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.870
• Publications: 0 publications found

Genes affected

ITPR1 (HGNC:6180): (inositol 1,4,5-trisphosphate receptor type 1) This gene encodes an intracellular receptor for inositol 1,4,5-trisphosphate. Upon stimulation by inositol 1,4,5-trisphosphate, this receptor mediates calcium release from the endoplasmic reticulum. Mutations in this gene cause spinocerebellar ataxia type 15, a disease associated with an heterogeneous group of cerebellar disorders. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Nov 2009]

ITPR1 Gene-Disease associations (from GenCC):

• aniridia-cerebellar ataxia-intellectual disability syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• spinocerebellar ataxia type 15/16

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33351305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.141C>A	p.Asn47Lys	missense_variant	Exon 4 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.141C>A	p.Asn47Lys	missense_variant	Exon 4 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.141C>A	p.Asn47Lys	missense_variant	Exon 4 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.141C>A	p.Asn47Lys	missense_variant	Exon 4 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.141C>A	p.Asn47Lys	missense_variant	Exon 4 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.141C>A	p.Asn47Lys	missense_variant	Exon 4 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.141C>A	p.Asn47Lys	missense_variant	Exon 4 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.141C>A	p.Asn47Lys	missense_variant	Exon 4 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.141C>A	p.Asn47Lys	missense_variant	Exon 4 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.141C>A	p.Asn47Lys	missense_variant	Exon 2 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.141C>A	p.Asn47Lys	missense_variant	Exon 4 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.141C>A	p.Asn47Lys	missense_variant	Exon 4 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461194 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726924

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111454

Other (OTH) AF: 0.0000166 AC: 1 AN: 60352

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 47 of the ITPR1 protein (p.Asn47Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ITPR1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;.;.;.;.;.;.;.;D;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;.
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.6	L;L;.;.;L;.;.;.;L;L;L
PhyloP100		0.87
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.3	N;N;.;N;N;.;N;.;.;.;N
REVEL	Uncertain	0.43
Sift	Benign	0.23	T;T;.;T;T;.;T;.;.;.;T
Sift4G	Benign	0.47	T;T;.;.;T;.;T;.;.;.;T
Polyphen		1.0, 0.13	.;.;.;.;.;.;D;.;B;.;.
Vest4		0.43
MutPred		0.52		Gain of methylation at N47 (P = 0.0199);Gain of methylation at N47 (P = 0.0199);Gain of methylation at N47 (P = 0.0199);Gain of methylation at N47 (P = 0.0199);Gain of methylation at N47 (P = 0.0199);Gain of methylation at N47 (P = 0.0199);Gain of methylation at N47 (P = 0.0199);Gain of methylation at N47 (P = 0.0199);Gain of methylation at N47 (P = 0.0199);Gain of methylation at N47 (P = 0.0199);Gain of methylation at N47 (P = 0.0199);
MVP		0.87
MPC		1.1
ClinPred		0.64	D
GERP RS		1.9
Varity_R		0.18
gMVP		0.71
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs370939479; hg19: chr3-4562756;