NM_001378452.1:c.141C>G

Variant names:

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

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>G​(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=0.32147962).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.141C>G	p.Asn47Lys	missense_variant	Exon 4 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.141C>G	p.Asn47Lys	missense_variant	Exon 4 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.141C>G	p.Asn47Lys	missense_variant	Exon 4 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.141C>G	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>G	p.Asn47Lys	missense_variant	Exon 4 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.141C>G	p.Asn47Lys	missense_variant	Exon 4 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.141C>G	p.Asn47Lys	missense_variant	Exon 4 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.141C>G	p.Asn47Lys	missense_variant	Exon 4 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.141C>G	p.Asn47Lys	missense_variant	Exon 4 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.141C>G	p.Asn47Lys	missense_variant	Exon 2 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.141C>G	p.Asn47Lys	missense_variant	Exon 4 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.141C>G	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: 0.00000275 AC XY: 2 AN XY: 726924

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000598 AC: 2 AN: 33468

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 60352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.002339), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.141C>G (p.N47K) alteration is located in exon 4 (coding exon 2) of the ITPR1 gene. This alteration results from a C to G substitution at nucleotide position 141, causing the asparagine (N) at amino acid position 47 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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	18
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;.;.;.;.;.;.;.;D;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;.
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.32	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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.71
Mutation Taster		=53/47	polymorphism

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: rs370939479; hg19: chr3-4562756;