3-4814550-G-T

Variant names:

• chr3-4814550-G-T
• rs901854
• NM_001378452.1:c.7689G>T

Variant summary

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

The NM_001378452.1(ITPR1):​c.7689G>T​(p.Lys2563Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K2563K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44
• Publications: 31 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)

ENSG00000235978 (HGNC:):

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=0.35599804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.7689G>T	p.Lys2563Asn	missense_variant	Exon 58 of 62	ENST00000649015.2	NP_001365381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.7689G>T	p.Lys2563Asn	missense_variant	Exon 58 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.7665G>T	p.Lys2555Asn	missense_variant	Exon 58 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.7662G>T	p.Lys2554Asn	missense_variant	Exon 58 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.7647G>T	p.Lys2549Asn	missense_variant	Exon 57 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.7644G>T	p.Lys2548Asn	missense_variant	Exon 57 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.7617G>T	p.Lys2539Asn	missense_variant	Exon 55 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.7545G>T	p.Lys2515Asn	missense_variant	Exon 55 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.7500G>T	p.Lys2500Asn	missense_variant	Exon 54 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.5451G>T	p.Lys1817Asn	missense_variant	Exon 38 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4866G>T	p.Lys1622Asn	missense_variant	Exon 35 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.4629G>T	p.Lys1543Asn	missense_variant	Exon 35 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1445478 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 718850

African (AFR) AF: 0.00 AC: 0 AN: 32746

American (AMR) AF: 0.00 AC: 0 AN: 44028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25466

East Asian (EAS) AF: 0.00 AC: 0 AN: 38708

South Asian (SAS) AF: 0.00 AC: 0 AN: 86070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101802

Other (OTH) AF: 0.00 AC: 0 AN: 59206

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 59277

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.82	.;.;.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.4	.;.;.;.;.;.;.;L;.;.;.
PhyloP100		1.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.4	N;N;.;N;.;N;.;.;.;N;.
REVEL	Uncertain	0.29
Sift	Benign	0.42	T;T;.;T;.;T;.;.;.;T;.
Sift4G	Benign	0.39	T;T;.;T;.;T;.;.;.;T;.
Polyphen		0.24, 0.019	.;.;.;.;.;B;.;B;.;.;.
Vest4		0.52
MutPred		0.48		.;.;.;.;.;.;.;Loss of methylation at K2563 (P = 0.0018);.;.;.;
MVP		0.82
MPC		2.1
ClinPred		0.79	D
GERP RS		3.1
PromoterAI		-0.22	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.96
Mutation Taster		=39/61	disease causing

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: rs901854; hg19: chr3-4856234;