Genetic Variant ENST00000446363.5:c.-397C>T (chr17-1716626-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000446363.5(WDR81):c.-397C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,551,704 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 6 hom. )

Consequence

WDR81
ENST00000446363.5 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.554

Publications

1 publications found

Variant links:

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 links:

MIR22HG (HGNC:28219): (MIR22 host gene) Predicted to act upstream of or within response to wounding. [provided by Alliance of Genome Resources, Apr 2022]

MIR22HG links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00956881).

BP6

Variant 17-1716626-C-T is Benign according to our data. Variant chr17-1716626-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2578776.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00209 (319/152396) while in subpopulation NFE AF = 0.00357 (243/68034). AF 95% confidence interval is 0.0032. There are 0 homozygotes in GnomAd4. There are 139 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000446363.5. 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_001163673.2		c.51C>T	p.Ser17Ser	synonymous	Exon 1 of 10	NP_001157145.1	Q562E7-5
	WDR81	NM_152348.4		c.-131C>T		5_prime_UTR	Exon 1 of 11	NP_689561.2	Q562E7-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WDR81	ENST00000446363.5	TSL:1	c.-397C>T		5_prime_UTR	Exon 1 of 9	ENSP00000401560.1	E9PDG3
WDR81	ENST00000468539.5	TSL:4	c.55C>T	p.Arg19Cys	missense	Exon 1 of 4	ENSP00000460742.1	I3L3U7
WDR81	ENST00000437219.6	TSL:2	c.51C>T	p.Ser17Ser	synonymous	Exon 1 of 10	ENSP00000391074.2	Q562E7-5

Frequencies

GnomAD3 genomes

AF:

0.00209

AC:

319

AN:

152278

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00216

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00357

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00187

AC:

293

AN:

156536

AF XY:

0.00183

show subpopulations

Gnomad AFR exome

AF:

0.000253

Gnomad AMR exome

AF:

0.000932

Gnomad ASJ exome

AF:

0.00141

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00250

Gnomad NFE exome

AF:

0.00315

Gnomad OTH exome

AF:

0.00159

GnomAD4 exome

AF:

0.00334

AC:

4676

AN:

1399308

Hom.:

Cov.:

AF XY:

0.00317

AC XY:

2190

AN XY:

690146

show subpopulations

African (AFR)

AF:

0.000411

AC:

AN:

31598

American (AMR)

AF:

0.00112

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00111

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00126

AC:

100

AN:

79230

European-Finnish (FIN)

AF:

0.00266

AC:

131

AN:

49206

Middle Eastern (MID)

AF:

0.000702

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00385

AC:

4157

AN:

1078958

Other (OTH)

AF:

0.00350

AC:

203

AN:

57998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

251

502

752

1003

1254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

174

348

522

696

870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00209

AC:

319

AN:

152396

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

139

AN XY:

74528

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41600

American (AMR)

AF:

0.00124

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00103

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00216

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00357

AC:

243

AN:

68034

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00211

Hom.:

Bravo

AF:

0.00184

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00346

AC:

ExAC

AF:

0.00118

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.030

FATHMM_MKL

Uncertain

0.80

MetaRNN

Benign

0.0096

PhyloP100

0.55

MVP

0.68

GERP RS

-1.1

PromoterAI

0.068

Neutral

(source)

Mutation Taster

=299/1

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over