9-25677730-A-T

Variant names:

• chr9-25677730-A-T
• rs762294270
• NM_001004125.3:c.583T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001004125.3(TUSC1):​c.583T>A​(p.Ser195Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,416,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S195A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TUSC1 NM_001004125.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.388
• Publications: 0 publications found

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]

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=0.032560706).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004125.3. 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
	TUSC1	NM_001004125.3	MANE Select	c.583T>A	p.Ser195Thr	missense	Exon 1 of 1	NP_001004125.2	Q2TAM9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUSC1	ENST00000358022.6	TSL:6 MANE Select	c.583T>A	p.Ser195Thr	missense	Exon 1 of 1	ENSP00000350716.4	Q2TAM9

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1416534 Hom.: 0 Cov.: 73 AF XY: 0.00000143 AC XY: 1 AN XY: 700450

African (AFR) AF: 0.00 AC: 0 AN: 32398

American (AMR) AF: 0.00 AC: 0 AN: 39228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25340

East Asian (EAS) AF: 0.00 AC: 0 AN: 37048

South Asian (SAS) AF: 0.00 AC: 0 AN: 80960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5220

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089192

Other (OTH) AF: 0.00 AC: 0 AN: 58500

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.0
DANN	Benign	0.57
DEOGEN2	Benign	0.0018	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.080	N
PhyloP100		-0.39
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.029
Sift	Benign	0.54	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.051
MutPred		0.062		Loss of glycosylation at S198 (P = 0.0622)
MVP		0.014
MPC		0.54
ClinPred		0.031	T
GERP RS		-4.5
Varity_R		0.050
gMVP		0.0052
Mutation Taster		=100/0	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: rs762294270; hg19: chr9-25677728;