1-3633478-C-A

Position:

• chr1-3633478-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_017818.4(WRAP73):​c.842G>T​(p.Ser281Ile) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: WRAP73 NM_017818.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0330

Genes affected

WRAP73 (HGNC:12759): (WD repeat containing, antisense to TP73) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Studies of the related mouse protein suggest that the encoded protein may play a role in the process of ossification. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity WRP73_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061454237).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRAP73	NM_017818.4	c.842G>T	p.Ser281Ile	missense_variant	9/12	ENST00000270708.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRAP73	ENST00000270708.12	c.842G>T	p.Ser281Ile	missense_variant	9/12	1	NM_017818.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

May 04, 2023

The c.842G>T (p.S281I) alteration is located in exon 9 (coding exon 9) of the WRAP73 gene. This alteration results from a G to T substitution at nucleotide position 842, causing the serine (S) at amino acid position 281 to be replaced by an isoleucine (I). 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	0.078
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.1
DANN	Benign	0.96
DEOGEN2	Benign	0.020	.;T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	.;M;.
MutationTaster	Benign	0.61	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.057
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.19	T;T;.
Polyphen		0.0, 0.0010	.;B;B
Vest4		0.24
MutPred		0.36		Loss of disorder (P = 0.0091);Loss of disorder (P = 0.0091);.;
MVP		0.12
MPC		0.24
ClinPred		0.26	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.47

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: chr1-3550042;