17-68430038-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_017983.7(WIPI1):c.923G>A(p.Arg308His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,614,146 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R308C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0056 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (9 hom.)
• Consequence: WIPI1 NM_017983.7 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.46

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006907344).
• BP6: Variant 17-68430038-C-T is Benign according to our data. Variant chr17-68430038-C-T is described in ClinVar as [Benign]. Clinvar id is 716489.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00561 (855/152282) while in subpopulation AFR AF= 0.0196 (815/41544). AF 95% confidence interval is 0.0185. There are 17 homozygotes in gnomad4. There are 416 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WIPI1	NM_017983.7	c.923G>A	p.Arg308His	missense_variant	9/13	ENST00000262139.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WIPI1	ENST00000262139.10	c.923G>A	p.Arg308His	missense_variant	9/13	1	NM_017983.7	P1
	ENST00000590353.1	n.173+16243C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00561 AC: 853 AN: 152164 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

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: 0.0000882

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00149 AC: 375 AN: 251424 Hom.: 2 AF XY: 0.00102 AC XY: 138 AN XY: 135880

Gnomad AFR exome AF: 0.0209

Gnomad AMR exome AF: 0.000839

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: 0.0000176

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000581 AC: 850 AN: 1461864 Hom.: 9 Cov.: 31 AF XY: 0.000466 AC XY: 339 AN XY: 727232

Gnomad4 AFR exome AF: 0.0217

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00561 AC: 855 AN: 152282 Hom.: 17 Cov.: 32 AF XY: 0.00559 AC XY: 416 AN XY: 74456

Gnomad4 AFR AF: 0.0196

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.000992 Hom.: 2

Bravo AF: 0.00672

ESP6500AA AF: 0.0243 AC: 107

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00200 AC: 243

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.027	T;.;T
Eigen	Benign	0.094
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.26	N;N;.
REVEL	Benign	0.076
Sift	Benign	0.24	T;T;.
Sift4G	Benign	0.29	T;T;T
Polyphen		0.14	B;.;.
Vest4		0.80
MVP		0.23
MPC		0.52
ClinPred		0.035	T
GERP RS		5.5
Varity_R		0.097
gMVP		0.52

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

Other links and lift over

dbSNP: rs36084378; hg19: chr17-66426179;