3-4670833-G-C

Variant names:

• chr3-4670833-G-C
• rs373694009
• NM_001378452.1:c.2111G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The ENST00000443694.5(ITPR1):​c.2066G>C​(p.Ser689Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000318 in 1,610,676 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S689N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: ITPR1 ENST00000443694.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 2.60
• Publications: 5 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: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01044482).
• BP6: Variant 3-4670833-G-C is Benign according to our data. Variant chr3-4670833-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 804931.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000348 (53/152190) while in subpopulation NFE AF = 0.000485 (33/68046). AF 95% confidence interval is 0.000354. There are 0 homozygotes in GnomAd4. There are 21 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: ENST00000443694.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	NM_001378452.1	MANE Select	c.2111G>C	p.Ser704Thr	missense	Exon 20 of 62	NP_001365381.1
	ITPR1	NM_001168272.2		c.2066G>C	p.Ser689Thr	missense	Exon 19 of 61	NP_001161744.1
	ITPR1	NM_001099952.4		c.2111G>C	p.Ser704Thr	missense	Exon 20 of 59	NP_001093422.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.2111G>C	p.Ser704Thr	missense	Exon 20 of 62	ENSP00000497605.1
	ITPR1	ENST00000354582.12	TSL:5	c.2111G>C	p.Ser704Thr	missense	Exon 20 of 62	ENSP00000346595.8
	ITPR1	ENST00000648266.1		c.2111G>C	p.Ser704Thr	missense	Exon 20 of 62	ENSP00000498014.1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0000654

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: 0.000485

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000205 AC: 50 AN: 243632 AF XY: 0.000212

Gnomad AFR exome AF: 0.0000667

Gnomad AMR exome AF: 0.0000885

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000407

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000315 AC: 459 AN: 1458486 Hom.: 0 Cov.: 32 AF XY: 0.000277 AC XY: 201 AN XY: 725126

African (AFR) AF: 0.0000598 AC: 2 AN: 33426

American (AMR) AF: 0.0000452 AC: 2 AN: 44272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.00 AC: 0 AN: 85376

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000388 AC: 431 AN: 1110484

Other (OTH) AF: 0.000398 AC: 24 AN: 60272

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74348

African (AFR) AF: 0.0000241 AC: 1 AN: 41444

American (AMR) AF: 0.0000654 AC: 1 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: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000313 Hom.: 0

Bravo AF: 0.000408

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000249 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000207 AC: 25

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	1	-	Gillespie syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	ITPR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.048	D
MutationAssessor	Benign	1.6	L
PhyloP100		2.6
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.35
Sift	Benign	0.17	T
Sift4G	Benign	0.20	T
Polyphen		0.0050	B
Vest4		0.16
MVP		0.81
MPC		0.73
ClinPred		0.038	T
GERP RS		4.6
PromoterAI		0.051	Neutral
Varity_R		0.30
gMVP		0.34
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs373694009; hg19: chr3-4712517;