X-54440751-G-C

Variant names:

• chrX-54440751-G-C
• rs773655172
• NM_058163.3:c.143G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001346790.2(TSR2):​c.-245G>C variant causes a 5 prime UTR premature start codon gain 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000013 (0 hom. 4 hem.)
• Consequence: TSR2 NM_001346790.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22
• Publications: 0 publications found

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)

ACMG classification

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_001346790.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	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

Sel.	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.: 23

GnomAD2 exomes AF: 0.0000118 AC: 2 AN: 169278 AF XY: 0.0000181

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: 14 AN: 1090453 Hom.: 0 Cov.: 30 AF XY: 0.0000112 AC XY: 4 AN XY: 356545

African (AFR) AF: 0.00 AC: 0 AN: 26144

American (AMR) AF: 0.00 AC: 0 AN: 34161

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18837

East Asian (EAS) AF: 0.00 AC: 0 AN: 29912

South Asian (SAS) AF: 0.00 AC: 0 AN: 52744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40284

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4081

European-Non Finnish (NFE) AF: 0.0000155 AC: 13 AN: 838562

Other (OTH) AF: 0.00 AC: 0 AN: 45728

GnomAD4 genome Cov.: 23

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	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Uncertain	0.53	D
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.2
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.082
Sift	Benign	0.12	T
Sift4G	Benign	0.24	T
Polyphen		0.0030	B
Vest4		0.24
MutPred		0.71		Loss of ubiquitination at K44 (P = 0.0777)
MVP		0.22
MPC		0.72
ClinPred		0.13	T
GERP RS		1.1
PromoterAI		-0.076	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.52
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs773655172; hg19: chrX-54467184;