rs1133400

Positions:

• chr10-132645884-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005539.5(INPP5A):​c.134A>G​(p.Lys45Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,611,502 control chromosomes in the GnomAD database, including 37,863 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.18 (2828 hom., cov: 33)
  • Exomes 𝑓: 0.21 (35035 hom.)
• Consequence: INPP5A NM_005539.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31

Genes affected

INPP5A (HGNC:6076): (inositol polyphosphate-5-phosphatase A) The protein encoded by this gene is a membrane-associated type I inositol 1,4,5-trisphosphate (InsP3) 5-phosphatase. InsP3 5-phosphatases hydrolyze Ins(1,4,5)P3, which mobilizes intracellular calcium and acts as a second messenger mediating cell responses to various stimulation. [provided by RefSeq, Jul 2008]

INPP5A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003926575).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INPP5A	NM_005539.5	c.134A>G	p.Lys45Arg	missense_variant	3/16	ENST00000368594.8	NP_005530.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INPP5A	ENST00000368594.8	c.134A>G	p.Lys45Arg	missense_variant	3/16	1	NM_005539.5	ENSP00000357583.3
INPP5A	ENST00000368593.7	c.134A>G	p.Lys45Arg	missense_variant	3/13	1		ENSP00000357582.3
INPP5A	ENST00000342652.6	c.47A>G	p.Lys16Arg	missense_variant	2/10	5		ENSP00000340707.6
INPP5A	ENST00000423490.5	c.75+37928A>G		intron_variant		5		ENSP00000390936.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27958 AN: 152014 Hom.: 2830 Cov.: 33

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.188

GnomAD3 exomes AF: 0.217 AC: 54398 AN: 250258 Hom.: 6378 AF XY: 0.215 AC XY: 29056 AN XY: 135356

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.294

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.353

Gnomad SAS exome AF: 0.221

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.214 AC: 312926 AN: 1459370 Hom.: 35035 Cov.: 32 AF XY: 0.213 AC XY: 154858 AN XY: 726088

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.288

Gnomad4 ASJ exome AF: 0.120

Gnomad4 EAS exome AF: 0.325

Gnomad4 SAS exome AF: 0.223

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.215

Gnomad4 OTH exome AF: 0.206

GnomAD4 genome AF: 0.184 AC: 27976 AN: 152132 Hom.: 2828 Cov.: 33 AF XY: 0.184 AC XY: 13717 AN XY: 74374

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.323

Gnomad4 SAS AF: 0.239

Gnomad4 FIN AF: 0.168

Gnomad4 NFE AF: 0.208

Gnomad4 OTH AF: 0.192

Alfa AF: 0.206 Hom.: 7953

Bravo AF: 0.187

TwinsUK AF: 0.214 AC: 793

ALSPAC AF: 0.211 AC: 814

ESP6500AA AF: 0.108 AC: 475

ESP6500EA AF: 0.203 AC: 1745

ExAC AF: 0.212 AC: 25772

Asia WGS AF: 0.276 AC: 957 AN: 3478

EpiCase AF: 0.205

EpiControl AF: 0.207

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.069
Sift	Benign	0.23	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.0	B;B
Vest4		0.056
MPC		0.48
ClinPred		0.012	T
GERP RS		-0.88
Varity_R		0.051
gMVP		0.34

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: rs1133400; hg19: chr10-134459388; COSMIC: COSV61246460;