3-4814550-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_001378452.1(ITPR1):​c.7689G>C​(p.Lys2563Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: 𝑓 0.0 (0 hom., cov: 24)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44

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]

ENSG00000235978 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3333463).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 149262 Hom.: 0 Cov.: 24 FAILED QC

Gnomad AFR AF: 0.00

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: 0.00000403 AC: 1 AN: 248248 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134688

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: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.92e-7 AC: 1 AN: 1445478 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 718850

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: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 149262 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 72584

Gnomad4 AFR AF: 0.00

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

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	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.82	.;.;.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.4	.;.;.;.;.;.;.;L;.;.;.
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		0.52	D
GERP RS		3.1
Varity_R		0.25
gMVP		0.96

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: rs901854; hg19: chr3-4856234;