rs1376457227

Variant names:

• chr15-53665757-T-C
• rs1376457227
• NM_182758.4:c.1777A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-53665757-T-C
• chr15-53665757-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_182758.4(WDR72):​c.1777A>G​(p.Arg593Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,410 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WDR72 NM_182758.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.41
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1777A>G	p.Arg593Gly	missense	Exon 14 of 20	NP_877435.3	Q3MJ13
	WDR72	NR_102334.2		n.2017A>G		non_coding_transcript_exon	Exon 14 of 20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR72	ENST00000360509.10	TSL:1 MANE Select	c.1777A>G	p.Arg593Gly	missense	Exon 14 of 20	ENSP00000353699.5	Q3MJ13
	WDR72	ENST00000396328.5	TSL:1	c.1777A>G	p.Arg593Gly	missense	Exon 14 of 20	ENSP00000379619.1	Q3MJ13
	WDR72	ENST00000559418.5	TSL:5	c.1807A>G	p.Arg603Gly	missense	Exon 13 of 19	ENSP00000452765.1	H0YKE0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251018 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461410 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726984

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111774

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Amelogenesis imperfecta hypomaturation type 2A3 (1)
1	-	-	Renal tubular acidosis, distal, 4, with hemolytic anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.32		Loss of sheet (P = 0.0315)
MVP		0.58
MPC		0.073
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.83
gMVP		0.67
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs1376457227; hg19: chr15-53957954;