X-54443414-G-C

Variant names:

• chrX-54443414-G-C
• NM_058163.3:c.187G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_058163.3(TSR2):​c.187G>C​(p.Asp63His) 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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: TSR2 NM_058163.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

Genes affected

TSR2 (HGNC:25455): (TSR2 ribosome maturation factor) The protein encoded by this gene appears to repress the transcription of NF-kappaB and may be involved in apoptosis. Defects in this gene are a cause of Diamond-Blackfan anemia. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19492489).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSR2	NM_058163.3	c.187G>C	p.Asp63His	missense_variant	Exon 3 of 5	ENST00000375151.5	NP_477511.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSR2	ENST00000375151.5	c.187G>C	p.Asp63His	missense_variant	Exon 3 of 5	1	NM_058163.3	ENSP00000364293.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 63 of the TSR2 protein (p.Asp63His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSR2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Uncertain	0.47	T
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.19
Sift	Benign	0.15	T
Sift4G	Benign	0.50	T
Polyphen		0.32	B
Vest4		0.25
MutPred		0.43		Loss of disorder (P = 0.1601);
MVP		0.49
MPC		1.3
ClinPred		0.46	T
GERP RS		3.2
Varity_R		0.28
gMVP		0.54

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: chrX-54469847; COSMIC: COSV64308617; COSMIC: COSV64308617;