9-136429700-G-C

Variant names:

• chr9-136429700-G-C
• NM_019892.6:c.1910C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_019892.6(INPP5E):​c.1910C>G​(p.Ser637Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: INPP5E NM_019892.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.97

Genes affected

INPP5E (HGNC:21474): (inositol polyphosphate-5-phosphatase E) The protein encoded by this gene is an 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. Studies of the mouse counterpart suggest that this protein may hydrolyze phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,5-bisphosphate on the cytoplasmic Golgi membrane and thereby regulate Golgi-vesicular trafficking. Mutations in this gene cause Joubert syndrome; a clinically and genetically heterogenous group of disorders characterized by midbrain-hindbrain malformation and various associated ciliopathies that include retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6	c.1910C>G	p.Ser637Cys	missense_variant	Exon 10 of 10	ENST00000371712.4	NP_063945.2
INPP5E	NM_001318502.2	c.1907C>G	p.Ser636Cys	missense_variant	Exon 10 of 10		NP_001305431.1
INPP5E	XM_017014926.2	c.*54C>G		3_prime_UTR_variant	Exon 10 of 10		XP_016870415.1
INPP5E	XM_047423603.1	c.*54C>G		3_prime_UTR_variant	Exon 10 of 10		XP_047279559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712.4	c.1910C>G	p.Ser637Cys	missense_variant	Exon 10 of 10	1	NM_019892.6	ENSP00000360777.3
INPP5E	ENST00000676019.1	c.1808C>G	p.Ser603Cys	missense_variant	Exon 10 of 10			ENSP00000501984.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461746 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1910C>G (p.S637C) alteration is located in exon 10 (coding exon 10) of the INPP5E gene. This alteration results from a C to G substitution at nucleotide position 1910, causing the serine (S) at amino acid position 637 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.011	D
Polyphen		0.98	D
Vest4		0.34
MutPred		0.34		Gain of sheet (P = 0.0085);
MVP		0.97
MPC		0.78
ClinPred		0.88	D
GERP RS		5.5
Varity_R		0.20
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-139324152;