rs199698357

Variant names:

• chr3-4683757-A-G
• rs199698357
• NM_001378452.1:c.3457A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS1

The NM_001378452.1(ITPR1):​c.3457A>G​(p.Met1153Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.39

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 Likely_benign. Variant got -6 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=0.08633149).
• BP6: Variant 3-4683757-A-G is Benign according to our data. Variant chr3-4683757-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 345726.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000985 (15/152252) while in subpopulation NFE AF= 0.000176 (12/68038). AF 95% confidence interval is 0.000102. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.3457A>G	p.Met1153Val	missense_variant	Exon 28 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.3412A>G	p.Met1138Val	missense_variant	Exon 27 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.3430A>G	p.Met1144Val	missense_variant	Exon 28 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.3385A>G	p.Met1129Val	missense_variant	Exon 27 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.3457A>G	p.Met1153Val	missense_variant	Exon 28 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.3430A>G	p.Met1144Val	missense_variant	Exon 28 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.3430A>G	p.Met1144Val	missense_variant	Exon 28 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.3412A>G	p.Met1138Val	missense_variant	Exon 27 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.3412A>G	p.Met1138Val	missense_variant	Exon 27 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.3385A>G	p.Met1129Val	missense_variant	Exon 25 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.3430A>G	p.Met1144Val	missense_variant	Exon 28 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.3385A>G	p.Met1129Val	missense_variant	Exon 27 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.1267A>G	p.Met423Val	missense_variant	Exon 9 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.757A>G	p.Met253Val	missense_variant	Exon 6 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.364A>G	p.Met122Val	missense_variant	Exon 4 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000297 AC: 74 AN: 249050 Hom.: 0 AF XY: 0.000296 AC XY: 40 AN XY: 135096

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: 0.000139

Gnomad NFE exome AF: 0.000629

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000183 AC: 268 AN: 1461686 Hom.: 0 Cov.: 32 AF XY: 0.000190 AC XY: 138 AN XY: 727122

Gnomad4 AFR exome AF: 0.0000597

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: 0.000131

Gnomad4 NFE exome AF: 0.000227

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74390

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000241 Hom.: 1

Bravo AF: 0.0000945

ExAC AF: 0.000480 AC: 58

EpiCase AF: 0.000327

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2019

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 29 Benign:1

Feb 09, 2018

Schule lab, Hertie Institute for Clinical Brain Research

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Autosomal dominant cerebellar ataxia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Benign	0.75
DEOGEN2	Benign	0.40	.;.;.;.;.;.;T;.;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.086	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.81	.;.;.;.;.;.;L;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.98	N;N;.;N;.;.;.;.;N;.
REVEL	Uncertain	0.39
Sift	Benign	0.42	T;T;.;T;.;.;.;.;T;.
Sift4G	Benign	0.36	T;T;.;T;.;.;.;.;T;.
Polyphen		0.0020	.;.;.;.;.;.;B;.;.;.
Vest4		0.40
MVP		0.80
MPC		0.75
ClinPred		0.049	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.26

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: rs199698357; hg19: chr3-4725441;