rs151330612

chr17-1728491-G-Achr17-1728491-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001163809.2(WDR81):c.3532G>A(p.Ala1178Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,598,926 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (2 hom.)
• Consequence: WDR81 NM_001163809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 1.79

Genes affected

WDR81 (HGNC:26600): (WD repeat domain 81) This gene encodes a multi-domain transmembrane protein which is predominantly expressed in the brain and is thought to play a role in endolysosomal trafficking. Mutations in this gene are associated with an autosomal recessive form of a syndrome exhibiting cerebellar ataxia, cognitive disability, and disequilibrium (CAMRQ2). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003869027).
• BP6: Variant 17-1728491-G-A is Benign according to our data. Variant chr17-1728491-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235691.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}. Variant chr17-1728491-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00123 (187/152334) while in subpopulation NFE AF= 0.00194 (132/68028). AF 95% confidence interval is 0.00167. There are 0 homozygotes in gnomad4. There are 94 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR81	NM_001163809.2	c.3532G>A	p.Ala1178Thr	missense_variant	1/10	ENST00000409644.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR81	ENST00000409644.6	c.3532G>A	p.Ala1178Thr	missense_variant	1/10	1	NM_001163809.2	P1
	ENST00000576540.1	n.296-2580C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 188 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00114 AC: 253 AN: 222296 Hom.: 0 AF XY: 0.00120 AC XY: 144 AN XY: 120266

Gnomad AFR exome AF: 0.000562

Gnomad AMR exome AF: 0.000949

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000556

Gnomad NFE exome AF: 0.00203

Gnomad OTH exome AF: 0.00106

GnomAD4 exome AF: 0.00175 AC: 2538 AN: 1446592 Hom.: 2 Cov.: 34 AF XY: 0.00166 AC XY: 1190 AN XY: 717956

Gnomad4 AFR exome AF: 0.000301

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.000116

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000611

Gnomad4 NFE exome AF: 0.00213

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.00126 AC XY: 94 AN XY: 74486

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00189 Hom.: 2

Bravo AF: 0.00126

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00102 AC: 123

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	WDR81: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 11, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 14, 2021	- -

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2;C4747885:Hydrocephalus, congenital, 3, with brain anomalies Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	1.2
Dann	Benign	0.93
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.38	N
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.47	N;N
REVEL	Benign	0.10
Sift	Benign	0.47	T;T
Sift4G	Benign	0.68	T;T
Vest4		0.082
MVP		0.13
MPC		0.38
ClinPred		0.0028	T
GERP RS		-0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.055

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

Publications

LitVar

Other links and lift over

dbSNP: rs151330612; hg19: chr17-1631785;