chr17-2324302-T-C

Variant names:

• chr17-2324302-T-C
• rs752262714
• NM_018128.5:c.2309A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018128.5(TSR1):​c.2309A>G​(p.Tyr770Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000213 in 1,410,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TSR1 NM_018128.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93
• Publications: 0 publications found

Genes affected

TSR1 (HGNC:25542): (TSR1 ribosome maturation factor) Enables RNA binding activity. Predicted to be involved in endonucleolytic cleavage of tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) and maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA). Predicted to be located in nucleolus. Predicted to be part of preribosome, small subunit precursor. [provided by Alliance of Genome Resources, Apr 2022]

SRR (HGNC:14398): (serine racemase) Enables several functions, including L-serine ammonia-lyase activity; PDZ domain binding activity; and anion binding activity. Involved in pyruvate biosynthetic process; response to lipopolysaccharide; and serine family amino acid metabolic process. Located in cytoplasm and neuronal cell body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018128.5. 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
	TSR1	NM_018128.5	MANE Select	c.2309A>G	p.Tyr770Cys	missense	Exon 15 of 15	NP_060598.3
	SRR	NM_021947.3	MANE Select	c.*429T>C		3_prime_UTR	Exon 8 of 8	NP_068766.1	Q9GZT4
	SRR	NM_001304803.1		c.*429T>C		3_prime_UTR	Exon 7 of 7	NP_001291732.1	Q3ZK31

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSR1	ENST00000301364.10	TSL:1 MANE Select	c.2309A>G	p.Tyr770Cys	missense	Exon 15 of 15	ENSP00000301364.4	Q2NL82
	SRR	ENST00000344595.10	TSL:1 MANE Select	c.*429T>C		3_prime_UTR	Exon 8 of 8	ENSP00000339435.5	Q9GZT4
	TSR1	ENST00000915544.1		c.2288A>G	p.Tyr763Cys	missense	Exon 15 of 15	ENSP00000585603.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000488 AC: 1 AN: 205052 AF XY: 0.00000912

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: 0.0000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1410702 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 698098

African (AFR) AF: 0.00 AC: 0 AN: 31382

American (AMR) AF: 0.00 AC: 0 AN: 34508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22566

East Asian (EAS) AF: 0.00 AC: 0 AN: 39440

South Asian (SAS) AF: 0.00 AC: 0 AN: 76416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5522

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1091130

Other (OTH) AF: 0.00 AC: 0 AN: 58172

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		3.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.5	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.85		Loss of phosphorylation at Y770 (P = 0.0418)
MVP		0.64
MPC		0.57
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.88

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: rs752262714; hg19: chr17-2227596;