X-54443418-A-G

Position:

• chrX-54443418-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_058163.3(TSR2):​c.191A>G​(p.Glu64Gly) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: TSR2 NM_058163.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.83

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 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, 0.897
• PP5: Variant X-54443418-A-G is Pathogenic according to our data. Variant chrX-54443418-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 187847.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-54443418-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSR2	NM_058163.3	c.191A>G	p.Glu64Gly	missense_variant	3/5	ENST00000375151.5	NP_477511.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSR2	ENST00000375151.5	c.191A>G	p.Glu64Gly	missense_variant	3/5	1	NM_058163.3	ENSP00000364293	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia 14 with mandibulofacial dysostosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2014

- -

Diamond-Blackfan anemia 15 with mandibulofacial dysostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

research

University of Washington Center for Mendelian Genomics, University of Washington

May 19, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.56		Loss of stability (P = 0.0948);
MVP		0.96
MPC		1.6
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.91
gMVP		0.81

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: rs786203996; hg19: chrX-54469851;