chr2-189465128-T-C

Position:

• chr2-189465128-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032168.3(WDR75):​c.1163T>C​(p.Ile388Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR75 NM_032168.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06

Genes affected

WDR75 (HGNC:25725): (WD repeat domain 75) Enables RNA binding activity. Involved in positive regulation of rRNA processing and positive regulation of transcription by RNA polymerase I. Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05958149).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR75	NM_032168.3	c.1163T>C	p.Ile388Thr	missense_variant	12/21	ENST00000314761.9
WDR75	NM_001303096.2	c.971T>C	p.Ile324Thr	missense_variant	13/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR75	ENST00000314761.9	c.1163T>C	p.Ile388Thr	missense_variant	12/21	1	NM_032168.3	P1
WDR75	ENST00000427960.5	c.*2527T>C		3_prime_UTR_variant, NMD_transcript_variant	12/21	1
WDR75	ENST00000436347.5	c.*927T>C		3_prime_UTR_variant, NMD_transcript_variant	13/22	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Mar 31, 2024

The c.1163T>C (p.I388T) alteration is located in exon 12 (coding exon 12) of the WDR75 gene. This alteration results from a T to C substitution at nucleotide position 1163, causing the isoleucine (I) at amino acid position 388 to be replaced by a threonine (T). 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	Benign	0.068
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Benign	0.73
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.85	N
MutationTaster	Benign	0.96	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.066
Sift	Benign	0.34	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.099
MutPred		0.53		Loss of stability (P = 0.0055);
MVP		0.043
MPC		0.21
ClinPred		0.75	D
GERP RS		4.3
Varity_R		0.030
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1686974974; hg19: chr2-190329854;