NM_003295.4:c.364A>G

Variant names:

• chr13-45339532-T-C
• rs768020738
• NM_003295.4:c.364A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_003295.4(TPT1):​c.364A>G​(p.Ile122Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000068 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: TPT1 NM_003295.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.88
• Publications: 0 publications found

Genes affected

TPT1 (HGNC:12022): (tumor protein, translationally-controlled 1) This gene encodes a protein that is a regulator of cellular growth and proliferation. Its mRNA is highly structured and contains an oligopyrimidine tract (5'-TOP) in its 5' untranslated region that functions to repress its translation under quiescent conditions. The encoded protein is involved in a variety of cellular pathways, including apoptosis, protein synthesis and cell division. It binds to and stabilizes microtubules, and removal of this protein through phosphorylation is required for progression through mitotic and meiotic cell divisions. This gene is known to play a role in carcinogenesis, and is upregulated in some cancer cells. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2017]

ENSG00000273149 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.116375834).
• BP6: Variant 13-45339532-T-C is Benign according to our data. Variant chr13-45339532-T-C is described in ClinVar as Benign. ClinVar VariationId is 2672289.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003295.4. 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
	TPT1	NM_003295.4	MANE Select	c.364A>G	p.Ile122Val	missense	Exon 4 of 6	NP_003286.1	P13693-1
	TPT1	NM_001286272.2		c.364A>G	p.Ile122Val	missense	Exon 4 of 6	NP_001273201.1	A0A0B4J2C3
	TPT1	NM_001286273.2		c.262A>G	p.Ile88Val	missense	Exon 3 of 5	NP_001273202.1	P13693-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPT1	ENST00000530705.6	TSL:1 MANE Select	c.364A>G	p.Ile122Val	missense	Exon 4 of 6	ENSP00000431872.2	P13693-1
	TPT1	ENST00000309246.9	TSL:1	c.364A>G	p.Ile122Val	missense	Exon 4 of 5	ENSP00000339051.4	Q5W0H4
	TPT1	ENST00000379056.5	TSL:1	c.262A>G	p.Ile88Val	missense	Exon 3 of 5	ENSP00000368345.1	P13693-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.000112 AC: 28 AN: 249312 AF XY: 0.000134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000585

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000681 AC: 99 AN: 1454322 Hom.: 1 Cov.: 30 AF XY: 0.0000928 AC XY: 67 AN XY: 722278

⚠️ 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: 33322

American (AMR) AF: 0.00 AC: 0 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26022

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39580

South Asian (SAS) AF: 0.000269 AC: 23 AN: 85660

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53268

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5746

European-Non Finnish (NFE) AF: 0.0000624 AC: 69 AN: 1106108

Other (OTH) AF: 0.0000499 AC: 3 AN: 60128

⚠️ 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.: 33

Alfa AF: 0.000814 Hom.: 0

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions as Germline

Significance: Benign

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	Benign	0.24
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.046
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.13	N
PhyloP100		1.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.082
Sift	Benign	0.87	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.22
MVP		0.12
MPC		0.34
ClinPred		0.054	T
GERP RS		4.8
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.15
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs768020738; hg19: chr13-45913667;