rs377577583

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-54440443-G-C
• chrX-54440443-G-A
• chrX-54440443-G-T

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. 14/20 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
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04404813).
• BS2: High AC in GnomAd4 at 11 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSR2	NM_058163.3	MANE Select	c.22G>C	p.Ala8Pro	missense	Exon 1 of 5	NP_477511.1	Q969E8
	TSR2	NM_001346789.2		c.22G>C	p.Ala8Pro	missense	Exon 1 of 5	NP_001333718.1
	TSR2	NM_001346790.2		c.-366G>C		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.22G>C	p.Ala8Pro	missense	Exon 1 of 5	ENSP00000364293.4	Q969E8
	TSR2	ENST00000908048.1		c.22G>C	p.Ala8Pro	missense	Exon 1 of 5	ENSP00000578107.1
	TSR2	ENST00000960847.1		c.22G>C	p.Ala8Pro	missense	Exon 1 of 5	ENSP00000630906.1

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

African (AFR) AF: 0.00 AC: 0 AN: 22829

American (AMR) AF: 0.00 AC: 0 AN: 20476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14577

East Asian (EAS) AF: 0.00 AC: 0 AN: 27258

South Asian (SAS) AF: 0.00 AC: 0 AN: 42005

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3782

European-Non Finnish (NFE) AF: 0.000227 AC: 183 AN: 804886

Other (OTH) 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

African (AFR) AF: 0.0000323 AC: 1 AN: 30980

American (AMR) AF: 0.0000940 AC: 1 AN: 10636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2661

East Asian (EAS) AF: 0.00 AC: 0 AN: 3577

South Asian (SAS) AF: 0.00 AC: 0 AN: 2758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6211

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000169 AC: 9 AN: 53249

Other (OTH) AF: 0.00 AC: 0 AN: 1516

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.65
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
PromoterAI		0.24	Neutral
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

Other links and lift over

dbSNP: rs377577583; hg19: chrX-54466876;