10-132749539-T-G

Variant names:

• chr10-132749539-T-G
• rs1846433487
• NM_005539.5:c.755T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005539.5(INPP5A):​c.755T>G​(p.Met252Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M252T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: INPP5A NM_005539.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.68
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5A	NM_005539.5	c.755T>G	p.Met252Arg	missense_variant	Exon 10 of 16	ENST00000368594.8	NP_005530.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5A	ENST00000368594.8	c.755T>G	p.Met252Arg	missense_variant	Exon 10 of 16	1	NM_005539.5	ENSP00000357583.3
INPP5A	ENST00000368593.7	c.755T>G	p.Met252Arg	missense_variant	Exon 10 of 13	1		ENSP00000357582.3
INPP5A	ENST00000498337.1	n.217T>G		non_coding_transcript_exon_variant	Exon 3 of 5	3
INPP5A	ENST00000342652.6	c.646-16234T>G		intron_variant	Intron 8 of 9	5		ENSP00000340707.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460598 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726590

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L;.
PhyloP100		5.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.16
Sift	Benign	0.54	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.92	P;D
Vest4		0.86
MutPred		0.59		Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);
MVP		0.21
MPC		0.90
ClinPred		0.77	D
GERP RS		5.1
Varity_R		0.59
gMVP		0.88
Mutation Taster		=66/34	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: rs1846433487; hg19: chr10-134563043;