Genetic Variant NM_058163.3:c.143G>C (chrX-54440751-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_058163.3(TSR2):c.143G>C(p.Gly48Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,090,453 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G48D) has been classified as Benign.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000013 ( 0 hom. 4 hem. )

Consequence

TSR2
NM_058163.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.22

Publications

0 publications found

Variant links:

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]

TSR2 Gene-Disease associations (from GenCC):

Diamond-Blackfan anemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Diamond-Blackfan anemia 14 with mandibulofacial dysostosis
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

TSR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25780618).

BS2

High AC in GnomAdExome4 at 14 AD,XL gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058163.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSR2	NM_058163.3	MANE Select	c.143G>C	p.Gly48Ala	missense	Exon 2 of 5	NP_477511.1	Q969E8
TSR2	NM_001346790.2		c.-245G>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	NP_001333719.1
TSR2	NM_001346791.2		c.-254G>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	NP_001333720.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSR2	ENST00000375151.5	TSL:1 MANE Select	c.143G>C	p.Gly48Ala	missense	Exon 2 of 5	ENSP00000364293.4	Q969E8
TSR2	ENST00000908048.1		c.143G>C	p.Gly48Ala	missense	Exon 2 of 5	ENSP00000578107.1
TSR2	ENST00000960847.1		c.143G>C	p.Gly48Ala	missense	Exon 2 of 5	ENSP00000630906.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000118

AC:

AN:

169278

AF XY:

0.0000181

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000128

AC:

AN:

1090453

Hom.:

Cov.:

AF XY:

0.0000112

AC XY:

AN XY:

356545

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26144

American (AMR)

AF:

0.00

AC:

AN:

34161

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18837

East Asian (EAS)

AF:

0.00

AC:

AN:

29912

South Asian (SAS)

AF:

0.00

AC:

AN:

52744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40284

Middle Eastern (MID)

AF:

0.000245

AC:

AN:

4081

European-Non Finnish (NFE)

AF:

0.0000155

AC:

AN:

838562

Other (OTH)

AF:

0.00

AC:

AN:

45728

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.53

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.62

M_CAP

Benign

0.0072

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

1.2

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.082

Sift

Benign

0.12

Sift4G

Benign

0.24

Polyphen

0.0030

Vest4

0.24

MutPred

0.71

Loss of ubiquitination at K44 (P = 0.0777)

MVP

0.22

MPC

0.72

ClinPred

0.13

GERP RS

1.1

PromoterAI

-0.076

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.24

gMVP

0.52

Mutation Taster

=88/12

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over