3-4814520-C-T

Variant names:

• chr3-4814520-C-T
• rs200562410
• NM_001378452.1:c.7659C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The ENST00000443694.5(ITPR1):​c.7614C>T​(p.Ser2538Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,558,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000049 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: ITPR1 ENST00000443694.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.188
• Publications: 1 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)

ENSG00000235978 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 3-4814520-C-T is Benign according to our data. Variant chr3-4814520-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 447600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.188 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000488 (6/123052) while in subpopulation EAS AF = 0.000837 (3/3586). AF 95% confidence interval is 0.000228. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 27. 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.7659C>T	p.Ser2553Ser	synonymous	Exon 58 of 62	NP_001365381.1
	ITPR1	NM_001168272.2		c.7614C>T	p.Ser2538Ser	synonymous	Exon 57 of 61	NP_001161744.1
	ITPR1	NM_001099952.4		c.7515C>T	p.Ser2505Ser	synonymous	Exon 55 of 59	NP_001093422.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.7659C>T	p.Ser2553Ser	synonymous	Exon 58 of 62	ENSP00000497605.1
	ITPR1	ENST00000354582.12	TSL:5	c.7635C>T	p.Ser2545Ser	synonymous	Exon 58 of 62	ENSP00000346595.8
	ITPR1	ENST00000648266.1		c.7632C>T	p.Ser2544Ser	synonymous	Exon 58 of 62	ENSP00000498014.1

Frequencies

GnomAD3 genomes AF: 0.0000488 AC: 6 AN: 123004 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000621

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000836

Gnomad SAS AF: 0.000274

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000442 AC: 11 AN: 249102 AF XY: 0.0000296

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000501

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000181 AC: 26 AN: 1435944 Hom.: 0 Cov.: 38 AF XY: 0.0000182 AC XY: 13 AN XY: 714062

African (AFR) AF: 0.0000310 AC: 1 AN: 32308

American (AMR) AF: 0.00 AC: 0 AN: 43558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25092

East Asian (EAS) AF: 0.000236 AC: 9 AN: 38086

South Asian (SAS) AF: 0.0000698 AC: 6 AN: 85984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.00000913 AC: 10 AN: 1095542

Other (OTH) AF: 0.00 AC: 0 AN: 58466

GnomAD4 genome AF: 0.0000488 AC: 6 AN: 123052 Hom.: 0 Cov.: 27 AF XY: 0.0000348 AC XY: 2 AN XY: 57448

African (AFR) AF: 0.0000620 AC: 2 AN: 32252

American (AMR) AF: 0.00 AC: 0 AN: 9860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3266

East Asian (EAS) AF: 0.000837 AC: 3 AN: 3586

South Asian (SAS) AF: 0.000274 AC: 1 AN: 3644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62452

Other (OTH) AF: 0.00 AC: 0 AN: 1680

Alfa AF: 0.0000461 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	12
DANN	Benign	0.97
PhyloP100		0.19
PromoterAI		-0.0084	Neutral

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: rs200562410; hg19: chr3-4856204; COSMIC: COSV57002869; COSMIC: COSV57002869;