chr3-4693543-C-G

Position:

• chr3-4693543-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001378452.1(ITPR1):​c.4083C>G​(p.Phe1361Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.39

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.4083C>G	p.Phe1361Leu	missense_variant	33/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.4038C>G	p.Phe1346Leu	missense_variant	32/61		NP_001161744.1
ITPR1	NM_001099952.4	c.4056C>G	p.Phe1352Leu	missense_variant	33/59		NP_001093422.2
ITPR1	NM_002222.7	c.4011C>G	p.Phe1337Leu	missense_variant	32/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.4083C>G	p.Phe1361Leu	missense_variant	33/62		NM_001378452.1	ENSP00000497605

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249286 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135240

Gnomad AFR exome AF: 0.00

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461662 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727122

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.2	.;.;.;.;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.8	D;D;.;D;.;.;.;.;D;.
REVEL	Pathogenic	0.76
Sift	Benign	0.12	T;T;.;T;.;.;.;.;T;.
Sift4G	Benign	0.17	T;T;.;T;.;.;.;.;T;.
Polyphen		1.0	.;.;.;.;.;.;D;.;.;.
Vest4		0.65
MutPred		0.69		.;.;.;.;.;.;Gain of MoRF binding (P = 0.2545);.;.;.;
MVP		0.84
MPC		1.9
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.65
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs763239856; hg19: chr3-4735227;