17-2324278-G-A

Position:

• chr17-2324278-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_018128.5(TSR1):​c.2333C>T​(p.Thr778Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,555,294 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (9 hom.)
• Consequence: TSR1 NM_018128.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 9.84

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

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012049884).
• BP6: Variant 17-2324278-G-A is Benign according to our data. Variant chr17-2324278-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3042039.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 254 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSR1	NM_018128.5	c.2333C>T	p.Thr778Ile	missense_variant	15/15	ENST00000301364.10	NP_060598.3
SRR	NM_021947.3	c.*405G>A		3_prime_UTR_variant	8/8	ENST00000344595.10	NP_068766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSR1	ENST00000301364.10	c.2333C>T	p.Thr778Ile	missense_variant	15/15	1	NM_018128.5	ENSP00000301364.4
SRR	ENST00000344595.10	c.*405G>A		3_prime_UTR_variant	8/8	1	NM_021947.3	ENSP00000339435.5

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 254 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00195 AC: 388 AN: 198782 Hom.: 1 AF XY: 0.00209 AC XY: 222 AN XY: 106190

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.00152

Gnomad ASJ exome AF: 0.00264

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00463

Gnomad FIN exome AF: 0.000961

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.00320

GnomAD4 exome AF: 0.00173 AC: 2423 AN: 1402992 Hom.: 9 Cov.: 31 AF XY: 0.00185 AC XY: 1280 AN XY: 693654

Gnomad4 AFR exome AF: 0.000290

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.00385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00539

Gnomad4 FIN exome AF: 0.00119

Gnomad4 NFE exome AF: 0.00152

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.00167 AC: 254 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74472

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00187 Hom.: 2

Bravo AF: 0.00158

ExAC AF: 0.00237 AC: 288

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TSR1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 21, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.33
Sift	Benign	0.040	D
Sift4G	Uncertain	0.036	D
Polyphen		0.78	P
Vest4		0.67
MVP		0.52
MPC		0.52
ClinPred		0.081	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.67
gMVP		0.72

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: rs141644586; hg19: chr17-2227572; COSMIC: COSV56786179; COSMIC: COSV56786179;