chr17-1728044-G-A

Variant names:

• chr17-1728044-G-A
• rs766140596
• NM_001163809.2:c.3085G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001163809.2(WDR81):​c.3085G>A​(p.Ala1029Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,558,088 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000057 (2 hom.)
• Consequence: WDR81 NM_001163809.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.822
• Publications: 0 publications found

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]

WDR81 Gene-Disease associations (from GenCC):

• cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• cerebellar ataxia, intellectual disability, and dysequilibrium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

WDR81-AS1 (HGNC:58142):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013398021).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001163809.2. 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
	WDR81	NM_001163809.2	MANE Select	c.3085G>A	p.Ala1029Thr	missense	Exon 1 of 10	NP_001157281.1	Q562E7-1
	WDR81	NM_152348.4		c.-69G>A		5_prime_UTR	Exon 2 of 11	NP_689561.2	Q562E7-3
	WDR81	NM_001163673.2		c.59-2336G>A		intron	N/A	NP_001157145.1	Q562E7-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR81	ENST00000409644.6	TSL:1 MANE Select	c.3085G>A	p.Ala1029Thr	missense	Exon 1 of 10	ENSP00000386609.1	Q562E7-1
	WDR81	ENST00000446363.5	TSL:1	c.-308-2711G>A		intron	N/A	ENSP00000401560.1	E9PDG3
	WDR81	ENST00000309182.9	TSL:2	c.-69G>A		5_prime_UTR	Exon 2 of 11	ENSP00000312074.5	Q562E7-3

Frequencies

GnomAD3 genomes AF: 0.0000206 AC: 3 AN: 145520 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000491

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000104 AC: 17 AN: 162840 AF XY: 0.000171

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000452

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000573 AC: 81 AN: 1412568 Hom.: 2 Cov.: 37 AF XY: 0.0000930 AC XY: 65 AN XY: 698608

African (AFR) AF: 0.00 AC: 0 AN: 32194

American (AMR) AF: 0.00 AC: 0 AN: 37040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25344

East Asian (EAS) AF: 0.00 AC: 0 AN: 36782

South Asian (SAS) AF: 0.000691 AC: 56 AN: 81006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.0000212 AC: 23 AN: 1087226

Other (OTH) AF: 0.0000342 AC: 2 AN: 58544

GnomAD4 genome AF: 0.0000206 AC: 3 AN: 145520 Hom.: 0 Cov.: 33 AF XY: 0.0000424 AC XY: 3 AN XY: 70818

African (AFR) AF: 0.0000246 AC: 1 AN: 40652

American (AMR) AF: 0.00 AC: 0 AN: 14358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3338

East Asian (EAS) AF: 0.00 AC: 0 AN: 4994

South Asian (SAS) AF: 0.000491 AC: 2 AN: 4074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64822

Other (OTH) AF: 0.00 AC: 0 AN: 2004

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000824 AC: 9

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.2
DANN	Benign	0.47
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N
PhyloP100		0.82
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.046
Sift	Benign	0.56	T
Sift4G	Benign	0.31	T
Vest4		0.061
MutPred		0.17		Gain of glycosylation at A1029 (P = 0.0053)
MVP		0.048
MPC		0.38
ClinPred		0.0092	T
GERP RS		-0.34
PromoterAI		0.0016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.17
Mutation Taster		=94/6	polymorphism

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: rs766140596; hg19: chr17-1631338;