chr3-4675201-C-T

Variant names:

• chr3-4675201-C-T
• rs201519806
• NM_001378452.1:c.2732C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_001378452.1(ITPR1):​c.2732C>T​(p.Ala911Val) variant causes a missense change. The variant allele was found at a frequency of 0.000323 in 1,611,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A911A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 4.45
• Publications: 10 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: G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 15/16

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07862571).
• BP6: Variant 3-4675201-C-T is Benign according to our data. Variant chr3-4675201-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 345716.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000408 (62/152070) while in subpopulation NFE AF = 0.00072 (49/68020). AF 95% confidence interval is 0.00056. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378452.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	NM_001378452.1	MANE Select	c.2732C>T	p.Ala911Val	missense	Exon 23 of 62	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.2687C>T	p.Ala896Val	missense	Exon 22 of 61	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.2732C>T	p.Ala911Val	missense	Exon 23 of 59	NP_001093422.2	Q14643-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.2732C>T	p.Ala911Val	missense	Exon 23 of 62	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.2732C>T	p.Ala911Val	missense	Exon 23 of 62	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.2732C>T	p.Ala911Val	missense	Exon 23 of 62	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 62 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000368 AC: 91 AN: 247512 AF XY: 0.000380

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000372

Gnomad NFE exome AF: 0.000675

Gnomad OTH exome AF: 0.000334

GnomAD4 exome AF: 0.000314 AC: 459 AN: 1459730 Hom.: 0 Cov.: 30 AF XY: 0.000340 AC XY: 247 AN XY: 726088

African (AFR) AF: 0.0000599 AC: 2 AN: 33386

American (AMR) AF: 0.0000450 AC: 2 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85756

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53360

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.000363 AC: 403 AN: 1111024

Other (OTH) AF: 0.000249 AC: 15 AN: 60314

GnomAD4 genome AF: 0.000408 AC: 62 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74264

African (AFR) AF: 0.0000966 AC: 4 AN: 41388

American (AMR) AF: 0.000393 AC: 6 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68020

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.000560 Hom.: 0

Bravo AF: 0.000351

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000257 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000314 AC: 38

EpiCase AF: 0.000491

EpiControl AF: 0.000416

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	1	-	Gillespie syndrome;C1847725:Spinocerebellar ataxia type 15/16;C1861732:Spinocerebellar ataxia type 29 (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	Spinocerebellar ataxia type 29 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.079	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.14	N
PhyloP100		4.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.21
Sift	Benign	0.44	T
Sift4G	Benign	0.37	T
Polyphen		0.69	P
Vest4		0.27
MVP		0.54
MPC		0.76
ClinPred		0.029	T
GERP RS		3.8
PromoterAI		-0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.054
gMVP		0.54
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs201519806; hg19: chr3-4716885; COSMIC: COSV56986903; COSMIC: COSV56986903;