6-169602278-A-T

Position:

• chr6-169602278-A-T

Variant summary

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

The NM_182552.5(WDR27):​c.2365T>A​(p.Cys789Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000353 in 1,415,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: WDR27 NM_182552.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35

Genes affected

WDR27 (HGNC:21248): (WD repeat domain 27) This gene encodes a protein with multiple WD repeats. Proteins with these repeats may form scaffolds for protein-protein interaction and play key roles in cell signalling. Alternative splicing results in multiple transcript variants, but the full-length structure of some of these variants cannot be determined. [provided by RefSeq, Nov 2015]

ENSG00000285733 (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, 0.75

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR27	NM_182552.5	c.2365T>A	p.Cys789Ser	missense_variant	23/26	ENST00000448612.6	NP_872358.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR27	ENST00000448612.6	c.2365T>A	p.Cys789Ser	missense_variant	23/26	1	NM_182552.5	ENSP00000416289.1
ENSG00000285733	ENST00000648086.1	c.375T>A	p.His125Gln	missense_variant	4/8			ENSP00000497979.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000353 AC: 5 AN: 1415134 Hom.: 0 Cov.: 30 AF XY: 0.00000429 AC XY: 3 AN XY: 699250

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: 0.00000368

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Sep 08, 2024

The c.2365T>A (p.C789S) alteration is located in exon 23 (coding exon 22) of the WDR27 gene. This alteration results from a T to A substitution at nucleotide position 2365, causing the cysteine (C) at amino acid position 789 to be replaced by a serine (S). 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
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Benign	0.97
Eigen	Benign	0.078
Eigen_PC	Benign	-0.038
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0034	T
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.98	T
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0050	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.76
MutPred		0.55		Gain of disorder (P = 0.0046);.;
MVP		0.12
MPC		0.13
ClinPred		0.76	D
GERP RS		4.6
gMVP		0.37

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: rs1390264295; hg19: chr6-170002374;