rs17730281

chr15-53615751-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182758.4(WDR72):c.2455C>T(p.Leu819Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,613,084 control chromosomes in the GnomAD database, including 46,614 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4079 hom., cov: 32)
  • Exomes 𝑓: 0.23 (42535 hom.)
• Consequence: WDR72 NM_182758.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.07

Genes affected

WDR72 (HGNC:26790): (WD repeat domain 72) This gene encodes a protein with eight WD-40 repeats. Mutations in this gene have been associated with amelogenesis imperfecta hypomaturation type 2A3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003987491).
• BP6: Variant 15-53615751-G-A is Benign according to our data. Variant chr15-53615751-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 262999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-53615751-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR72	NM_182758.4	c.2455C>T	p.Leu819Phe	missense_variant	15/20	ENST00000360509.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR72	ENST00000360509.10	c.2455C>T	p.Leu819Phe	missense_variant	15/20	1	NM_182758.4	P4
WDR72	ENST00000396328.5	c.2455C>T	p.Leu819Phe	missense_variant	15/20	1		P4
WDR72	ENST00000559418.5	c.2485C>T	p.Leu829Phe	missense_variant	14/19	5
WDR72	ENST00000557913.5	c.2446C>T	p.Leu816Phe	missense_variant	15/20	5		A1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33384 AN: 151756 Hom.: 4066 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.0955

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.215

GnomAD3 exomes AF: 0.261 AC: 65410 AN: 250214 Hom.: 9935 AF XY: 0.254 AC XY: 34412 AN XY: 135250

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.406

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.464

Gnomad SAS exome AF: 0.238

Gnomad FIN exome AF: 0.257

Gnomad NFE exome AF: 0.222

Gnomad OTH exome AF: 0.237

GnomAD4 exome AF: 0.234 AC: 341825 AN: 1461210 Hom.: 42535 Cov.: 37 AF XY: 0.234 AC XY: 169815 AN XY: 726922

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.398

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.425

Gnomad4 SAS exome AF: 0.243

Gnomad4 FIN exome AF: 0.257

Gnomad4 NFE exome AF: 0.225

Gnomad4 OTH exome AF: 0.232

GnomAD4 genome AF: 0.220 AC: 33406 AN: 151874 Hom.: 4079 Cov.: 32 AF XY: 0.226 AC XY: 16753 AN XY: 74212

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.308

Gnomad4 ASJ AF: 0.0955

Gnomad4 EAS AF: 0.459

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.261

Gnomad4 NFE AF: 0.223

Gnomad4 OTH AF: 0.217

Alfa AF: 0.220 Hom.: 7116

Bravo AF: 0.223

TwinsUK AF: 0.217 AC: 806

ALSPAC AF: 0.235 AC: 906

ESP6500AA AF: 0.158 AC: 692

ESP6500EA AF: 0.221 AC: 1896

ExAC AF: 0.254 AC: 30891

Asia WGS AF: 0.344 AC: 1197 AN: 3478

EpiCase AF: 0.206

EpiControl AF: 0.211

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Amelogenesis imperfecta hypomaturation type 2A3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 02, 2020

This variant is associated with the following publications: (PMID: 22797727) -

Amelogenesis Imperfecta, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.33	T;.;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.86	D
MetaRNN	Benign	0.0040	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	2.9	M;.;M;.
MutationTaster	Benign	0.0018	P;P;P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.7	D;D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.39
MPC		0.086
ClinPred		0.024	T
GERP RS		5.7
Varity_R		0.57
gMVP		0.51

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: rs17730281; hg19: chr15-53907948; COSMIC: COSV64747627; COSMIC: COSV64747627;