9-25677933-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001004125.3(TUSC1):​c.380G>T​(p.Arg127Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,558,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

TUSC1
NM_001004125.3 missense

Scores

1
18

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.305
Variant links:
Genes affected
TUSC1 (HGNC:31010): (tumor suppressor candidate 1) This gene is located within the region of chromosome 9p that harbors tumor suppressor genes critical in carcinogenesis. It is an intronless gene which is downregulated in non-small-cell lung cancer and small-cell lung cancer cell lines, suggesting that it may play a role in lung tumorigenesis. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.026680708).
BP6
Variant 9-25677933-C-A is Benign according to our data. Variant chr9-25677933-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3184935.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TUSC1NM_001004125.3 linkc.380G>T p.Arg127Leu missense_variant Exon 1 of 1 ENST00000358022.6 NP_001004125.2 Q2TAM9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TUSC1ENST00000358022.6 linkc.380G>T p.Arg127Leu missense_variant Exon 1 of 1 6 NM_001004125.3 ENSP00000350716.4 Q2TAM9

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152206
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000104
AC:
16
AN:
154444
Hom.:
0
AF XY:
0.000106
AC XY:
9
AN XY:
84798
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000262
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000173
AC:
244
AN:
1406744
Hom.:
0
Cov.:
74
AF XY:
0.000172
AC XY:
120
AN XY:
695914
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000248
Gnomad4 NFE exome
AF:
0.000220
Gnomad4 OTH exome
AF:
0.0000684
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152206
Hom.:
0
Cov.:
34
AF XY:
0.0000672
AC XY:
5
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000181
Hom.:
0
Bravo
AF:
0.0000982
ExAC
AF:
0.000134
AC:
15

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Jun 06, 2022
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.062
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.76
CADD
Benign
2.4
DANN
Benign
0.61
DEOGEN2
Benign
0.0034
T
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.015
N
LIST_S2
Benign
0.32
T
M_CAP
Benign
0.0021
T
MetaRNN
Benign
0.027
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.69
N
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-0.65
N
REVEL
Benign
0.027
Sift
Benign
0.32
T
Sift4G
Benign
0.39
T
Polyphen
0.0
B
Vest4
0.10
MVP
0.014
MPC
0.74
ClinPred
0.038
T
GERP RS
-0.89
Varity_R
0.035
gMVP
0.026

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs770050897; hg19: chr9-25677931; API