rs690346

Variant names:

• chr15-53716648-T-C
• rs690346
• NM_182758.4:c.298A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M100R) has been classified as Uncertain significance.

• 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
• Publications: 27 publications found

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]

WDR72 Gene-Disease associations (from GenCC):

• amelogenesis imperfecta

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• amelogenesis imperfecta hypomaturation type 2A3

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• amelogenesis imperfecta type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• renal tubular acidosis

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 263001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182758.4. 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
	WDR72	NM_182758.4	MANE Select	c.298A>G	p.Met100Val	missense	Exon 4 of 20	NP_877435.3	Q3MJ13
	WDR72	NR_102334.2		n.538A>G		non_coding_transcript_exon	Exon 4 of 20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR72	ENST00000360509.10	TSL:1 MANE Select	c.298A>G	p.Met100Val	missense	Exon 4 of 20	ENSP00000353699.5	Q3MJ13
	WDR72	ENST00000396328.5	TSL:1	c.298A>G	p.Met100Val	missense	Exon 4 of 20	ENSP00000379619.1	Q3MJ13
	WDR72	ENST00000559418.5	TSL:5	c.298A>G	p.Met100Val	missense	Exon 3 of 19	ENSP00000452765.1	H0YKE0

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

GnomAD2 exomes AF: 0.990 AC: 248821 AN: 251214 AF XY: 0.993

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 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

African (AFR) AF: 0.868 AC: 28917 AN: 33322

American (AMR) AF: 0.994 AC: 44450 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 26069 AN: 26092

East Asian (EAS) AF: 1.00 AC: 39678 AN: 39678

South Asian (SAS) AF: 1.00 AC: 86126 AN: 86164

European-Finnish (FIN) AF: 1.00 AC: 53410 AN: 53410

Middle Eastern (MID) AF: 0.996 AC: 5739 AN: 5760

European-Non Finnish (NFE) AF: 1.00 AC: 1107070 AN: 1107360

Other (OTH) AF: 0.991 AC: 59692 AN: 60208

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

African (AFR) AF: 0.870 AC: 36134 AN: 41516

American (AMR) AF: 0.987 AC: 15097 AN: 15294

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3471 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5174 AN: 5174

South Asian (SAS) AF: 0.999 AC: 4815 AN: 4818

European-Finnish (FIN) AF: 1.00 AC: 10620 AN: 10620

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 68002 AN: 68038

Other (OTH) AF: 0.969 AC: 2045 AN: 2110

Alfa AF: 0.985 Hom.: 143292

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Amelogenesis imperfecta hypomaturation type 2A3 (1)
-	-	1	Amelogenesis Imperfecta, Recessive (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	5.6e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.57	N
PhyloP100		0.92
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.013
Sift	Benign	0.87	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.11
MPC		0.012
ClinPred		0.0020	T
GERP RS		2.3
Varity_R		0.046
gMVP		0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs690346; hg19: chr15-54008845; COSMIC: COSV107472719;