3-4639465-A-G

Position:

• chr3-4639465-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001378452.1(ITPR1):​c.361A>G​(p.Ile121Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,326 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.46

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ITPR1. . Gene score misZ 5.5951 (greater than the threshold 3.09). Trascript score misZ 6.2026 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25599712).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.361A>G	p.Ile121Val	missense_variant	6/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.361A>G	p.Ile121Val	missense_variant	6/61		NP_001161744.1
ITPR1	NM_001099952.4	c.361A>G	p.Ile121Val	missense_variant	6/59		NP_001093422.2
ITPR1	NM_002222.7	c.361A>G	p.Ile121Val	missense_variant	6/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.361A>G	p.Ile121Val	missense_variant	6/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.361A>G	p.Ile121Val	missense_variant	6/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.361A>G	p.Ile121Val	missense_variant	6/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.361A>G	p.Ile121Val	missense_variant	6/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.361A>G	p.Ile121Val	missense_variant	6/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.361A>G	p.Ile121Val	missense_variant	4/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.361A>G	p.Ile121Val	missense_variant	6/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.361A>G	p.Ile121Val	missense_variant	6/58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000512 AC: 1 AN: 195454 Hom.: 0 AF XY: 0.00000962 AC XY: 1 AN XY: 103970

Gnomad AFR exome AF: 0.0000886

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1424284 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 704990

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74484

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000836 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	.;.;.;.;.;.;.;.;D;.;.
Eigen	Benign	0.033
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;.
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.2	L;L;.;.;L;.;.;.;L;L;L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.24	N;N;.;N;N;.;N;.;.;.;N
REVEL	Uncertain	0.39
Sift	Benign	0.50	T;T;.;T;T;.;T;.;.;.;T
Sift4G	Benign	0.59	T;T;.;.;T;.;T;.;.;.;T
Polyphen		0.013, 0.10	.;.;.;.;.;.;B;.;B;.;.
Vest4		0.71
MutPred		0.60		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.55
MPC		1.4
ClinPred		0.36	T
GERP RS		5.3
Varity_R		0.11
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs532037891; hg19: chr3-4681149;