rs883541

Positions:

• chr17-68452981-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017983.7(WIPI1):​c.92C>T​(p.Thr31Ile) variant causes a missense change. The variant allele was found at a frequency of 0.765 in 1,611,838 control chromosomes in the GnomAD database, including 473,991 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.78 (46068 hom., cov: 31)
  • Exomes 𝑓: 0.76 (427923 hom.)
• Consequence: WIPI1 NM_017983.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.41

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]

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]

WIPI1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.61811E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.837 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WIPI1	NM_017983.7	c.92C>T	p.Thr31Ile	missense_variant	2/13	ENST00000262139.10	NP_060453.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WIPI1	ENST00000262139.10	c.92C>T	p.Thr31Ile	missense_variant	2/13	1	NM_017983.7	ENSP00000262139.4

Frequencies

GnomAD3 genomes AF: 0.775 AC: 117822 AN: 151970 Hom.: 46017 Cov.: 31

Gnomad AFR AF: 0.844

Gnomad AMI AF: 0.655

Gnomad AMR AF: 0.701

Gnomad ASJ AF: 0.772

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.780

Gnomad FIN AF: 0.748

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.774

Gnomad OTH AF: 0.762

GnomAD3 exomes AF: 0.738 AC: 185431 AN: 251262 Hom.: 69573 AF XY: 0.744 AC XY: 101094 AN XY: 135840

Gnomad AFR exome AF: 0.846

Gnomad AMR exome AF: 0.625

Gnomad ASJ exome AF: 0.770

Gnomad EAS exome AF: 0.515

Gnomad SAS exome AF: 0.783

Gnomad FIN exome AF: 0.756

Gnomad NFE exome AF: 0.774

Gnomad OTH exome AF: 0.752

GnomAD4 exome AF: 0.764 AC: 1114762 AN: 1459750 Hom.: 427923 Cov.: 38 AF XY: 0.764 AC XY: 555177 AN XY: 726288

Gnomad4 AFR exome AF: 0.851

Gnomad4 AMR exome AF: 0.639

Gnomad4 ASJ exome AF: 0.771

Gnomad4 EAS exome AF: 0.548

Gnomad4 SAS exome AF: 0.775

Gnomad4 FIN exome AF: 0.758

Gnomad4 NFE exome AF: 0.773

Gnomad4 OTH exome AF: 0.759

GnomAD4 genome AF: 0.775 AC: 117926 AN: 152088 Hom.: 46068 Cov.: 31 AF XY: 0.771 AC XY: 57318 AN XY: 74356

Gnomad4 AFR AF: 0.844

Gnomad4 AMR AF: 0.701

Gnomad4 ASJ AF: 0.772

Gnomad4 EAS AF: 0.537

Gnomad4 SAS AF: 0.780

Gnomad4 FIN AF: 0.748

Gnomad4 NFE AF: 0.774

Gnomad4 OTH AF: 0.761

Alfa AF: 0.767 Hom.: 114403

Bravo AF: 0.773

TwinsUK AF: 0.770 AC: 2856

ALSPAC AF: 0.766 AC: 2953

ESP6500AA AF: 0.828 AC: 3648

ESP6500EA AF: 0.770 AC: 6620

ExAC AF: 0.747 AC: 90657

Asia WGS AF: 0.662 AC: 2304 AN: 3478

EpiCase AF: 0.773

EpiControl AF: 0.773

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0000026	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.1	N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	3.1	N
REVEL	Benign	0.12
Sift	Benign	0.23	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.094
MPC		0.42
ClinPred		0.023	T
GERP RS		5.0
Varity_R		0.039
gMVP		0.090

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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

Other links and lift over

dbSNP: rs883541; hg19: chr17-66449122; COSMIC: COSV50929487; COSMIC: COSV50929487;