17-68430114-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017983.7(WIPI1):ā€‹c.847T>Cā€‹(p.Phe283Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000818 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000085 ( 0 hom., cov: 32)
Exomes š‘“: 0.000081 ( 0 hom. )

Consequence

WIPI1
NM_017983.7 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.10
Variant links:
Genes affected
WIPI1 (HGNC:25471): (WD repeat domain, phosphoinositide interacting 1) This gene encodes a WD40 repeat protein. Members of the WD40 repeat family are key components of many essential biologic functions. They regulate the assembly of multiprotein complexes by presenting a beta-propeller platform for simultaneous and reversible protein-protein interactions. Members of the WIPI subfamily of WD40 repeat proteins have a 7-bladed propeller structure and contain a conserved motif for interaction with phospholipids. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]
ARSG (HGNC:24102): (arylsulfatase G) The protein encoded by this gene belongs to the sulfatase enzyme family. Sulfatases hydrolyze sulfate esters from sulfated steroids, carbohydrates, proteoglycans, and glycolipids. They are involved in hormone biosynthesis, modulation of cell signaling, and degradation of macromolecules. This protein displays arylsulfatase activity at acidic pH, as is typical of lysosomal sulfatases, and has been shown to localize in the lysosomes. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2012]
PRKAR1A (HGNC:9388): (protein kinase cAMP-dependent type I regulatory subunit alpha) cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by activating the cAMP-dependent protein kinase, which transduces the signal through phosphorylation of different target proteins. The inactive kinase holoenzyme is a tetramer composed of two regulatory and two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits have been identified in humans. This gene encodes one of the regulatory subunits. This protein was found to be a tissue-specific extinguisher that down-regulates the expression of seven liver genes in hepatoma x fibroblast hybrids. Mutations in this gene cause Carney complex (CNC). This gene can fuse to the RET protooncogene by gene rearrangement and form the thyroid tumor-specific chimeric oncogene known as PTC2. A nonconventional nuclear localization sequence (NLS) has been found for this protein which suggests a role in DNA replication via the protein serving as a nuclear transport protein for the second subunit of the Replication Factor C (RFC40). Several alternatively spliced transcript variants encoding two different isoforms have been observed. [provided by RefSeq, Jan 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07072961).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WIPI1NM_017983.7 linkuse as main transcriptc.847T>C p.Phe283Leu missense_variant 9/13 ENST00000262139.10 NP_060453.3 Q5MNZ9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WIPI1ENST00000262139.10 linkuse as main transcriptc.847T>C p.Phe283Leu missense_variant 9/131 NM_017983.7 ENSP00000262139.4 Q5MNZ9-1

Frequencies

GnomAD3 genomes
AF:
0.0000855
AC:
13
AN:
152054
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000107
AC:
27
AN:
251314
Hom.:
0
AF XY:
0.000140
AC XY:
19
AN XY:
135838
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000238
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000814
AC:
119
AN:
1461844
Hom.:
0
Cov.:
31
AF XY:
0.0000935
AC XY:
68
AN XY:
727230
show subpopulations
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:
0.000103
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000855
AC:
13
AN:
152054
Hom.:
0
Cov.:
32
AF XY:
0.0000943
AC XY:
7
AN XY:
74264
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000197
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000128
Hom.:
0
Bravo
AF:
0.000147
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.000115
AC:
14
EpiCase
AF:
0.000273
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 23, 2023The c.847T>C (p.F283L) alteration is located in exon 9 (coding exon 9) of the WIPI1 gene. This alteration results from a T to C substitution at nucleotide position 847, causing the phenylalanine (F) at amino acid position 283 to be replaced by a leucine (L). 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
Pathogenic
0.83
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
19
DANN
Benign
0.86
DEOGEN2
Benign
0.010
T;.;T
Eigen
Benign
-0.44
Eigen_PC
Benign
-0.27
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.54
T;T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.071
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.3
L;.;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
0.11
N;N;.
REVEL
Benign
0.099
Sift
Benign
1.0
T;T;.
Sift4G
Benign
1.0
T;T;T
Polyphen
0.0
B;.;.
Vest4
0.41
MutPred
0.39
Loss of sheet (P = 0.0181);.;.;
MVP
0.082
MPC
0.46
ClinPred
0.11
T
GERP RS
1.9
Varity_R
0.10
gMVP
0.32

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs191306252; hg19: chr17-66426255; API