3-4645653-G-T

Variant names:

• chr3-4645653-G-T
• rs549363319
• NM_001378452.1:c.780G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001378452.1(ITPR1):​c.780G>T​(p.Gln260His) 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 1,461,096 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.46

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ITPR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 5.5951 (above the threshold of 3.09). Trascript score misZ: 6.2026 (above the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.780G>T	p.Gln260His	missense_variant	Exon 10 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.780G>T	p.Gln260His	missense_variant	Exon 10 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.780G>T	p.Gln260His	missense_variant	Exon 10 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.780G>T	p.Gln260His	missense_variant	Exon 10 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.780G>T	p.Gln260His	missense_variant	Exon 10 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.780G>T	p.Gln260His	missense_variant	Exon 10 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.780G>T	p.Gln260His	missense_variant	Exon 10 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.780G>T	p.Gln260His	missense_variant	Exon 10 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.780G>T	p.Gln260His	missense_variant	Exon 10 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.780G>T	p.Gln260His	missense_variant	Exon 8 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.780G>T	p.Gln260His	missense_variant	Exon 10 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.780G>T	p.Gln260His	missense_variant	Exon 10 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248096 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134548

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: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461096 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726792

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Benign	0.71
DEOGEN2	Uncertain	0.73	.;.;.;.;.;.;.;.;D;.;.
Eigen	Benign	-0.086
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;.
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.8	L;L;.;.;L;.;.;.;L;L;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.2	N;N;.;N;N;.;D;.;.;.;N
REVEL	Pathogenic	0.66
Sift	Benign	0.46	T;T;.;T;T;.;T;.;.;.;T
Sift4G	Benign	0.54	T;T;.;.;T;.;T;.;.;.;T
Polyphen		0.97, 0.92	.;.;.;.;.;.;D;.;P;.;.
Vest4		0.48
MutPred		0.49		Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);
MVP		0.92
MPC		1.7
ClinPred		0.50	T
GERP RS		2.2
Varity_R		0.16
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs549363319; hg19: chr3-4687337;