chrX-54440443-G-C

Variant names:

• chrX-54440443-G-C
• rs377577583
• NM_058163.3:c.22G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_058163.3(TSR2):​c.22G>C​(p.Ala8Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,127,308 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 54 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00019 (0 hom. 49 hem.)
• Consequence: TSR2 NM_058163.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.653

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04404813).
• BS2: High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSR2	NM_058163.3	c.22G>C	p.Ala8Pro	missense_variant	Exon 1 of 5	ENST00000375151.5	NP_477511.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSR2	ENST00000375151.5	c.22G>C	p.Ala8Pro	missense_variant	Exon 1 of 5	1	NM_058163.3	ENSP00000364293.4

Frequencies

GnomAD3 genomes AF: 0.0000978 AC: 11 AN: 112508 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000940

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000169

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000470 AC: 4 AN: 85108 AF XY: 0.00

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: 0.000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000194 AC: 197 AN: 1014800 Hom.: 0 Cov.: 30 AF XY: 0.000153 AC XY: 49 AN XY: 319730

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 22829

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 20476

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 14577

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 27258

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 42005

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 36630

Gnomad4 NFE exome AF: 0.000227 AC: 183 AN: 804886

Gnomad4 Remaining exome AF: 0.000331 AC: 14 AN: 42357

GnomAD4 genome AF: 0.0000978 AC: 11 AN: 112508 Hom.: 0 Cov.: 23 AF XY: 0.000144 AC XY: 5 AN XY: 34640

Gnomad4 AFR AF: 0.0000323 AC: 0.0000322789 AN: 0.0000322789

Gnomad4 AMR AF: 0.0000940 AC: 0.0000940203 AN: 0.0000940203

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000169 AC: 0.000169017 AN: 0.000169017

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.000125

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000301 AC: 2

ExAC AF: 0.0000851 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.22G>C (p.A8P) alteration is located in exon 1 (coding exon 1) of the TSR2 gene. This alteration results from a G to C substitution at nucleotide position 22, causing the alanine (A) at amino acid position 8 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Nov 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 8 of the TSR2 protein (p.Ala8Pro). This variant is present in population databases (rs377577583, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with TSR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 2262503). 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 tolerated. 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	0.10
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.0
DANN	Benign	0.84
DEOGEN2	Benign	0.024	T
FATHMM_MKL	Benign	0.00038	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.050
Sift	Benign	0.27	T
Sift4G	Benign	0.23	T
Polyphen		0.23	B
Vest4		0.14
MVP		0.25
MPC		0.70
ClinPred		0.041	T
GERP RS		-0.54
Varity_R		0.084
gMVP		0.71
Mutation Taster		=98/2	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

Publications

LitVar

Other links and lift over

dbSNP: rs377577583; hg19: chrX-54466876;