17-1513957-C-G

Variant names:

• chr17-1513957-C-G
• NM_016532.4:c.67G>C
• INPP5K p.Val23Leu

Variant summary

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

The NM_130766.3(INPP5K):​c.-162G>C variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: INPP5K NM_130766.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.30
• Publications: 0 publications found

Genes affected

INPP5K (HGNC:33882): (inositol polyphosphate-5-phosphatase K) This gene encodes a protein with 5-phosphatase activity toward polyphosphate inositol. The protein localizes to the cytosol in regions lacking actin stress fibers. It is thought that this protein may negatively regulate the actin cytoskeleton. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]

INPP5K Gene-Disease associations (from GenCC):

• congenital muscular dystrophy with cataracts and intellectual disability

  Inheritance: AR Classification: STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Marinesco-Sjogren syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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, 0.846

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130766.3. 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
	INPP5K	NM_016532.4	MANE Select	c.67G>C	p.Val23Leu	missense	Exon 2 of 12	NP_057616.2
	INPP5K	NM_001135642.2		c.-162G>C		5_prime_UTR_premature_start_codon_gain	Exon 4 of 14	NP_001129114.1	Q9BT40-2
	INPP5K	NM_130766.3		c.-162G>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 13	NP_570122.1	Q9BT40-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5K	ENST00000421807.7	TSL:1 MANE Select	c.67G>C	p.Val23Leu	missense	Exon 2 of 12	ENSP00000413937.2	Q9BT40-1
	INPP5K	ENST00000320345.10	TSL:5	c.-162G>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 13	ENSP00000318476.6	Q9BT40-2
	INPP5K	ENST00000406424.8	TSL:5	c.-162G>C		5_prime_UTR_premature_start_codon_gain	Exon 4 of 14	ENSP00000385177.4	Q9BT40-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.3
PrimateAI	Benign	0.44	T
Sift4G	Pathogenic	0.0	D
Varity_R		0.77
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-1417251;