X-54440433-T-A

Variant names:

• chrX-54440433-T-A
• rs750620605
• NM_058163.3:c.12T>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_058163.3(TSR2):​c.12T>A​(p.Ala4Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000991 in 1,009,514 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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. Synonymous variant affecting the same amino acid position (i.e. A4A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.9e-7 (0 hom. 0 hem.)
• Consequence: TSR2 NM_058163.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.15
• 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSR2	NM_058163.3	MANE Select	c.12T>A	p.Ala4Ala	synonymous	Exon 1 of 5	NP_477511.1	Q969E8
	TSR2	NM_001346789.2		c.12T>A	p.Ala4Ala	synonymous	Exon 1 of 5	NP_001333718.1
	TSR2	NM_001346790.2		c.-376T>A		5_prime_UTR	Exon 1 of 5	NP_001333719.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSR2	ENST00000375151.5	TSL:1 MANE Select	c.12T>A	p.Ala4Ala	synonymous	Exon 1 of 5	ENSP00000364293.4	Q969E8
	TSR2	ENST00000908048.1		c.12T>A	p.Ala4Ala	synonymous	Exon 1 of 5	ENSP00000578107.1
	TSR2	ENST00000960847.1		c.12T>A	p.Ala4Ala	synonymous	Exon 1 of 5	ENSP00000630906.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.91e-7 AC: 1 AN: 1009514 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 316278

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22808

American (AMR) AF: 0.0000508 AC: 1 AN: 19697

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14528

East Asian (EAS) AF: 0.00 AC: 0 AN: 26972

South Asian (SAS) AF: 0.00 AC: 0 AN: 41404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36133

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3755

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 802039

Other (OTH) AF: 0.00 AC: 0 AN: 42178

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.1
DANN	Benign	0.76
PhyloP100		-1.1
PromoterAI		0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs750620605; hg19: chrX-54466866;