chr1-111448712-C-T

Position:

• chr1-111448712-C-T

Variant summary

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

The NM_024102.4(WDR77):​c.208G>A​(p.Glu70Lys) variant causes a missense change involving the alteration of a 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR77 NM_024102.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

Genes affected

WDR77 (HGNC:29652): (WD repeat domain 77) The protein encoded by this gene is an androgen receptor coactivator that forms a complex with protein arginine methyltransferase 5, which modifies specific arginines to dimethylarginines in several spliceosomal Sm proteins. The encoded protein may be involved in the early stages of prostate cancer, with most of the protein being nuclear-localized in benign cells but cytoplasmic in cancer cells. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

WDR77 (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, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR77	NM_024102.4	c.208G>A	p.Glu70Lys	missense_variant	2/10	ENST00000235090.10	NP_077007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR77	ENST00000235090.10	c.208G>A	p.Glu70Lys	missense_variant	2/10	1	NM_024102.4	ENSP00000235090.5
WDR77	ENST00000449340.1	c.16G>A	p.Glu6Lys	missense_variant	1/9	5		ENSP00000409300.1
WDR77	ENST00000459665.1	n.180G>A		non_coding_transcript_exon_variant	1/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Dec 05, 2024

The c.208G>A (p.E70K) alteration is located in exon 2 (coding exon 2) of the WDR77 gene. This alteration results from a G to A substitution at nucleotide position 208, causing the glutamic acid (E) at amino acid position 70 to be replaced by a lysine (K). 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	0.89
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.39
Sift	Benign	0.29	T
Sift4G	Benign	0.081	T
Polyphen		1.0	D
Vest4		0.78
MutPred		0.43		Gain of ubiquitination at E70 (P = 0.0177);
MVP		0.85
MPC		1.0
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1653164273; hg19: chr1-111991334;