rs690346

Positions:

• chr15-53716648-T-C

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.298A>G​(p.Met100Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.993 in 1,608,956 control chromosomes in the GnomAD database, including 793,903 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70788 hom., cov: 33)
  • Exomes 𝑓: 1.0 (723115 hom.)
• Consequence: WDR72 NM_182758.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.922

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=5.5697984E-7).
• BP6: Variant 15-53716648-T-C is Benign according to our data. Variant chr15-53716648-T-C is described in ClinVar as [Benign]. Clinvar id is 263001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-53716648-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR72	NM_182758.4	c.298A>G	p.Met100Val	missense_variant	4/20	ENST00000360509.10	NP_877435.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR72	ENST00000360509.10	c.298A>G	p.Met100Val	missense_variant	4/20	1	NM_182758.4	ENSP00000353699	P4

Frequencies

GnomAD3 genomes AF: 0.963 AC: 146480 AN: 152130 Hom.: 70760 Cov.: 33

Gnomad AFR AF: 0.871

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.987

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.969

GnomAD3 exomes AF: 0.990 AC: 248821 AN: 251214 Hom.: 123361 AF XY: 0.993 AC XY: 134800 AN XY: 135762

Gnomad AFR exome AF: 0.869

Gnomad AMR exome AF: 0.995

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.995

GnomAD4 exome AF: 0.996 AC: 1451151 AN: 1456708 Hom.: 723115 Cov.: 36 AF XY: 0.997 AC XY: 722662 AN XY: 725032

Gnomad4 AFR exome AF: 0.868

Gnomad4 AMR exome AF: 0.994

Gnomad4 ASJ exome AF: 0.999

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.991

GnomAD4 genome AF: 0.963 AC: 146563 AN: 152248 Hom.: 70788 Cov.: 33 AF XY: 0.964 AC XY: 71733 AN XY: 74434

Gnomad4 AFR AF: 0.870

Gnomad4 AMR AF: 0.987

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.969

Alfa AF: 0.992 Hom.: 117472

Bravo AF: 0.958

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3853

ESP6500AA AF: 0.880 AC: 3862

ESP6500EA AF: 1.00 AC: 8585

ExAC AF: 0.988 AC: 119977

Asia WGS AF: 0.995 AC: 3461 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

Amelogenesis Imperfecta, Recessive Benign:1

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	0.047
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.82
DEOGEN2	Benign	0.0014	T;.;T;.;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.25	.;T;T;T;T
MetaRNN	Benign	5.6e-7	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.57	N;.;N;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.0	N;N;N;N;N
REVEL	Benign	0.013
Sift	Benign	0.87	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;.;B;.;.
Vest4		0.11
MPC		0.012
ClinPred		0.0020	T
GERP RS		2.3
Varity_R		0.046
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs690346; hg19: chr15-54008845;