X-54443461-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_058163.3(TSR2):c.234T>C(p.Asp78=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00434 in 1,205,507 control chromosomes in the GnomAD database, including 15 homozygotes. There are 1,772 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (0 hom., 166 hem., cov: 23)
  • Exomes 𝑓: 0.0043 (15 hom. 1606 hem.)
• Consequence: TSR2 NM_058163.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.69

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant X-54443461-T-C is Benign according to our data. Variant chrX-54443461-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 709009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-54443461-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00431 (4716/1093692) while in subpopulation MID AF= 0.0274 (113/4119). AF 95% confidence interval is 0.0233. There are 15 homozygotes in gnomad4_exome. There are 1606 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 166 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSR2	NM_058163.3	c.234T>C	p.Asp78=	synonymous_variant	3/5	ENST00000375151.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSR2	ENST00000375151.5	c.234T>C	p.Asp78=	synonymous_variant	3/5	1	NM_058163.3	P1

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 520 AN: 111760 Hom.: 0 Cov.: 23 AF XY: 0.00489 AC XY: 166 AN XY: 33924

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.00783

Gnomad ASJ AF: 0.00792

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00188

Gnomad FIN AF: 0.00460

Gnomad MID AF: 0.0292

Gnomad NFE AF: 0.00609

Gnomad OTH AF: 0.00659

GnomAD3 exomes AF: 0.00450 AC: 790 AN: 175563 Hom.: 2 AF XY: 0.00482 AC XY: 291 AN XY: 60431

Gnomad AFR exome AF: 0.000631

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.00690

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00165

Gnomad FIN exome AF: 0.00572

Gnomad NFE exome AF: 0.00625

Gnomad OTH exome AF: 0.00888

GnomAD4 exome AF: 0.00431 AC: 4716 AN: 1093692 Hom.: 15 Cov.: 29 AF XY: 0.00447 AC XY: 1606 AN XY: 359390

Gnomad4 AFR exome AF: 0.00168

Gnomad4 AMR exome AF: 0.00339

Gnomad4 ASJ exome AF: 0.00799

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00197

Gnomad4 FIN exome AF: 0.00645

Gnomad4 NFE exome AF: 0.00435

Gnomad4 OTH exome AF: 0.00581

GnomAD4 genome AF: 0.00463 AC: 518 AN: 111815 Hom.: 0 Cov.: 23 AF XY: 0.00488 AC XY: 166 AN XY: 33989

Gnomad4 AFR AF: 0.000974

Gnomad4 AMR AF: 0.00782

Gnomad4 ASJ AF: 0.00792

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00188

Gnomad4 FIN AF: 0.00460

Gnomad4 NFE AF: 0.00609

Gnomad4 OTH AF: 0.00651

Alfa AF: 0.00623 Hom.: 84

Bravo AF: 0.00527

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TSR2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Diamond-Blackfan anemia 14 with mandibulofacial dysostosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 16, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	4.3
Dann	Benign	0.67

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: rs36032873; hg19: chrX-54469894;