rs748329888

Variant names:

• chr17-68430158-C-T
• rs748329888
• NM_017983.7:c.803G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-68430158-C-T
• chr17-68430158-C-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017983.7(WIPI1):​c.803G>A​(p.Arg268Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,459,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: WIPI1 NM_017983.7 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40
• Publications: 2 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]

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]

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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053223252).

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.803G>A	p.Arg268Gln	missense splice_region	Exon 9 of 13	NP_060453.3
	WIPI1	NM_001320772.2		c.557G>A	p.Arg186Gln	missense splice_region	Exon 8 of 12	NP_001307701.1	G5EA37
	ARSG	NM_001352905.2		c.*43+9652C>T		intron	N/A	NP_001339834.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WIPI1	ENST00000262139.10	TSL:1 MANE Select	c.803G>A	p.Arg268Gln	missense splice_region	Exon 9 of 13	ENSP00000262139.4	Q5MNZ9-1
	WIPI1	ENST00000891619.1		c.803G>A	p.Arg268Gln	missense splice_region	Exon 9 of 13	ENSP00000561678.1
	WIPI1	ENST00000959788.1		c.803G>A	p.Arg268Gln	missense splice_region	Exon 9 of 12	ENSP00000629847.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 249188 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000881

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1459634 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726112

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.0000451 AC: 2 AN: 44298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5490

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111106

Other (OTH) AF: 0.0000166 AC: 1 AN: 60254

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.62
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.99	L
PhyloP100		2.4
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.038
Sift	Benign	0.61	T
Sift4G	Benign	0.56	T
Polyphen		0.0030	B
Vest4		0.16
MutPred		0.28		Loss of sheet (P = 0.0457)
MVP		0.29
MPC		0.46
ClinPred		0.30	T
GERP RS		4.6
Varity_R		0.067
gMVP		0.16

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

Other links and lift over

dbSNP: rs748329888; hg19: chr17-66426299;