rs883541

Variant names:

• chr17-68452981-G-A
• rs883541
• NM_017983.7:c.92C>T

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 47 publications found

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]

PRKAR1A Gene-Disease associations (from GenCC):

• Acrodysostosis 1 with or without hormone resistance

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• acrodysostosis with multiple hormone resistance

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• Carney complex, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• pigmented nodular adrenocortical disease, primary, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
• acrodysostosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Carney complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial myxoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• primary pigmented nodular adrenocortical disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000267009 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017983.7. 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
	WIPI1	NM_017983.7	MANE Select	c.92C>T	p.Thr31Ile	missense	Exon 2 of 13	NP_060453.3
	PRKAR1A	NM_001278433.2		c.-7+39186G>A		intron	N/A	NP_001265362.1	B2R5T5
	WIPI1	NM_001320772.2		c.-83-2084C>T		intron	N/A	NP_001307701.1	G5EA37

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WIPI1	ENST00000262139.10	TSL:1 MANE Select	c.92C>T	p.Thr31Ile	missense	Exon 2 of 13	ENSP00000262139.4	Q5MNZ9-1
	WIPI1	ENST00000891619.1		c.92C>T	p.Thr31Ile	missense	Exon 2 of 13	ENSP00000561678.1
	WIPI1	ENST00000959788.1		c.92C>T	p.Thr31Ile	missense	Exon 2 of 12	ENSP00000629847.1

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

GnomAD2 exomes AF: 0.738 AC: 185431 AN: 251262 AF XY: 0.744

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 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

African (AFR) AF: 0.851 AC: 28461 AN: 33454

American (AMR) AF: 0.639 AC: 28587 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.771 AC: 20146 AN: 26122

East Asian (EAS) AF: 0.548 AC: 21746 AN: 39670

South Asian (SAS) AF: 0.775 AC: 66848 AN: 86210

European-Finnish (FIN) AF: 0.758 AC: 40416 AN: 53296

Middle Eastern (MID) AF: 0.803 AC: 4607 AN: 5736

European-Non Finnish (NFE) AF: 0.773 AC: 858186 AN: 1110222

Other (OTH) AF: 0.759 AC: 45765 AN: 60324

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

African (AFR) AF: 0.844 AC: 35039 AN: 41494

American (AMR) AF: 0.701 AC: 10700 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.772 AC: 2680 AN: 3470

East Asian (EAS) AF: 0.537 AC: 2774 AN: 5168

South Asian (SAS) AF: 0.780 AC: 3763 AN: 4824

European-Finnish (FIN) AF: 0.748 AC: 7898 AN: 10558

Middle Eastern (MID) AF: 0.796 AC: 234 AN: 294

European-Non Finnish (NFE) AF: 0.774 AC: 52636 AN: 68000

Other (OTH) AF: 0.761 AC: 1605 AN: 2110

Alfa AF: 0.769 Hom.: 208576

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 v4.9

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
PhyloP100		6.4
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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