14-63598917-A-T

Position:

• chr14-63598917-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_080666.4(WDR89):​c.1026T>A​(p.Asp342Glu) 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 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WDR89 NM_080666.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

Genes affected

WDR89 (HGNC:20489): (WD repeat domain 89)

ENSG00000258800 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR89	NM_080666.4	c.1026T>A	p.Asp342Glu	missense_variant	3/3	ENST00000620954.2	NP_542397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR89	ENST00000620954.2	c.1026T>A	p.Asp342Glu	missense_variant	3/3	6	NM_080666.4	ENSP00000480112.1
WDR89	ENST00000267522.7	c.1026T>A	p.Asp342Glu	missense_variant	3/3	1		ENSP00000267522.3
WDR89	ENST00000394942.2	c.1026T>A	p.Asp342Glu	missense_variant	2/2	5		ENSP00000378399.2
ENSG00000258800	ENST00000553983.1	n.44A>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2023

The c.1026T>A (p.D342E) alteration is located in exon 3 (coding exon 1) of the WDR89 gene. This alteration results from a T to A substitution at nucleotide position 1026, causing the aspartic acid (D) at amino acid position 342 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	.;T;.
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.0	M;M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.6	D;.;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.047	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.87
MutPred		0.60		Gain of disorder (P = 0.1674);Gain of disorder (P = 0.1674);Gain of disorder (P = 0.1674);
MVP		0.83
MPC		0.53
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.63
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-64065635;