NM_005539.5:c.214G>T

Variant names:

• chr10-132645964-G-T
• rs747952207
• NM_005539.5:c.214G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005539.5(INPP5A):​c.214G>T​(p.Val72Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,140 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. V72I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: INPP5A NM_005539.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.43
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5A	NM_005539.5	c.214G>T	p.Val72Phe	missense_variant	Exon 3 of 16	ENST00000368594.8	NP_005530.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5A	ENST00000368594.8	c.214G>T	p.Val72Phe	missense_variant	Exon 3 of 16	1	NM_005539.5	ENSP00000357583.3
INPP5A	ENST00000368593.7	c.214G>T	p.Val72Phe	missense_variant	Exon 3 of 13	1		ENSP00000357582.3
INPP5A	ENST00000342652.6	c.127G>T	p.Val43Phe	missense_variant	Exon 2 of 10	5		ENSP00000340707.6
INPP5A	ENST00000423490.5	c.75+38008G>T		intron_variant	Intron 2 of 5	5		ENSP00000390936.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458140 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725590

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108918

Other (OTH) AF: 0.00 AC: 0 AN: 60260

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.0096	T
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.0	L;.
PhyloP100		5.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.27
Sift	Benign	0.14	T;T
Sift4G	Benign	0.28	T;T
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.72		Loss of ubiquitination at K73 (P = 0.1055);Loss of ubiquitination at K73 (P = 0.1055);
MVP		0.26
MPC		1.8
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.43
gMVP		0.83
Mutation Taster		=41/59	disease causing

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: rs747952207; hg19: chr10-134459468;