17-68443464-T-C

Variant names:

• chr17-68443464-T-C
• rs2909207
• NM_017983.7:c.430+1029A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017983.7(WIPI1):​c.430+1029A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 152,158 control chromosomes in the GnomAD database, including 47,572 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.79 (47572 hom., cov: 33)
• Consequence: WIPI1 NM_017983.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.88
• Publications: 9 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: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.844 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WIPI1	NM_017983.7	MANE Select	c.430+1029A>G		intron	N/A	NP_060453.3
	ARSG	NM_001352910.2		c.*41+2640T>C		intron	N/A	NP_001339839.1
	PRKAR1A	NM_001278433.2		c.-7+29669T>C		intron	N/A	NP_001265362.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WIPI1	ENST00000262139.10	TSL:1 MANE Select	c.430+1029A>G		intron	N/A	ENSP00000262139.4
	WIPI1	ENST00000546360.5	TSL:2	c.184+1029A>G		intron	N/A	ENSP00000437345.1
	ENSG00000267009	ENST00000586515.5	TSL:5	n.540+22958T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.789 AC: 119906 AN: 152040 Hom.: 47513 Cov.: 33

Gnomad AFR AF: 0.851

Gnomad AMI AF: 0.655

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.772

Gnomad EAS AF: 0.587

Gnomad SAS AF: 0.776

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.775

Gnomad OTH AF: 0.771

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.789 AC: 120021 AN: 152158 Hom.: 47572 Cov.: 33 AF XY: 0.785 AC XY: 58367 AN XY: 74386

African (AFR) AF: 0.851 AC: 35346 AN: 41524

American (AMR) AF: 0.809 AC: 12351 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.772 AC: 2678 AN: 3470

East Asian (EAS) AF: 0.586 AC: 3037 AN: 5182

South Asian (SAS) AF: 0.776 AC: 3741 AN: 4822

European-Finnish (FIN) AF: 0.732 AC: 7748 AN: 10580

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

European-Non Finnish (NFE) AF: 0.775 AC: 52662 AN: 67988

Other (OTH) AF: 0.770 AC: 1627 AN: 2112

Alfa AF: 0.783 Hom.: 79120

Bravo AF: 0.798

Asia WGS AF: 0.679 AC: 2364 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.026
DANN	Benign	0.40
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2909207; hg19: chr17-66439605;