rs6416452

Positions:

• chr15-53702296-A-C
• chr15-53702296-A-G
• chr15-53702296-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_182758.4(WDR72):​c.1407T>G​(p.Tyr469Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y469Y) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: WDR72 NM_182758.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR72	NM_182758.4	c.1407T>G	p.Tyr469Ter	stop_gained	12/20	ENST00000360509.10	NP_877435.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR72	ENST00000360509.10	c.1407T>G	p.Tyr469Ter	stop_gained	12/20	1	NM_182758.4	ENSP00000353699	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	2.1e-20	P;P;P;P
Vest4		0.37
GERP RS		-2.0

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: rs6416452; hg19: chr15-53994493;