rs61757110

Variant names:

• chr3-4693723-C-G
• rs61757110
• NM_001378452.1:c.4263C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-4693723-C-G
• chr3-4693723-C-T
• chr3-4693723-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378452.1(ITPR1):​c.4263C>G​(p.His1421Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,612,892 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H1421H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0050 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.56
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009713441).
• BP6: Variant 3-4693723-C-G is Benign according to our data. Variant chr3-4693723-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 345736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00503 (766/152348) while in subpopulation AFR AF = 0.014 (582/41592). AF 95% confidence interval is 0.0131. There are 7 homozygotes in GnomAd4. There are 351 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

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.4263C>G	p.His1421Gln	missense	Exon 33 of 62	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.4218C>G	p.His1406Gln	missense	Exon 32 of 61	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.4236C>G	p.His1412Gln	missense	Exon 33 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.4263C>G	p.His1421Gln	missense	Exon 33 of 62	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.4236C>G	p.His1412Gln	missense	Exon 33 of 62	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.4236C>G	p.His1412Gln	missense	Exon 33 of 62	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.00505 AC: 768 AN: 152230 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00215 AC: 531 AN: 246696 AF XY: 0.00180

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.00475

Gnomad ASJ exome AF: 0.00230

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000895

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.00126 AC: 1845 AN: 1460544 Hom.: 5 Cov.: 31 AF XY: 0.00122 AC XY: 888 AN XY: 726432

African (AFR) AF: 0.0162 AC: 542 AN: 33446

American (AMR) AF: 0.00515 AC: 229 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.00314 AC: 82 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86118

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53354

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.000691 AC: 768 AN: 1111296

Other (OTH) AF: 0.00297 AC: 179 AN: 60354

GnomAD4 genome AF: 0.00503 AC: 766 AN: 152348 Hom.: 7 Cov.: 32 AF XY: 0.00471 AC XY: 351 AN XY: 74498

African (AFR) AF: 0.0140 AC: 582 AN: 41592

American (AMR) AF: 0.00673 AC: 103 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68030

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00606

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00213 AC: 259

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	10
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.90	D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0097	T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		-1.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.37		Loss of catalytic residue at D1423 (P = 0.1755)
MVP		0.85
MPC		1.5
ClinPred		0.12	T
GERP RS		-9.2
Varity_R		0.68
gMVP		0.74
Mutation Taster		=98/2	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: rs61757110; hg19: chr3-4735407;