1-3631576-C-G

Position:

• chr1-3631576-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_017818.4(WRAP73):​c.1130G>C​(p.Arg377Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: WRAP73 NM_017818.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.55

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRAP73	NM_017818.4	c.1130G>C	p.Arg377Pro	missense_variant	11/12	ENST00000270708.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRAP73	ENST00000270708.12	c.1130G>C	p.Arg377Pro	missense_variant	11/12	1	NM_017818.4	P1
WRAP73	ENST00000378322.7	c.1130G>C	p.Arg377Pro	missense_variant	11/11	1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 80

GnomAD4 genome Cov.: 34

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 21, 2024

The c.1130G>C (p.R377P) alteration is located in exon 11 (coding exon 11) of the WRAP73 gene. This alteration results from a G to C substitution at nucleotide position 1130, causing the arginine (R) at amino acid position 377 to be replaced by a proline (P). 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	0.73
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Pathogenic	2.9	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.061	T;T
Polyphen		0.99	.;D
Vest4		0.68
MutPred		0.74		Gain of disorder (P = 0.2801);Gain of disorder (P = 0.2801);
MVP		0.54
MPC		0.46
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.82

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: chr1-3548140;