chr9-25678092-C-A

Variant names:

• chr9-25678092-C-A
• rs1404601896
• NM_001004125.3:c.221G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001004125.3(TUSC1):​c.221G>T​(p.Arg74Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,074 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TUSC1 NM_001004125.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.221G>T	p.Arg74Leu	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.221G>T	p.Arg74Leu	missense	Exon 1 of 1	ENSP00000350716.4	Q2TAM9

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435074 Hom.: 0 Cov.: 43 AF XY: 0.00000140 AC XY: 1 AN XY: 712896

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000305 AC: 1 AN: 32822

American (AMR) AF: 0.00 AC: 0 AN: 43492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25674

East Asian (EAS) AF: 0.00 AC: 0 AN: 38858

South Asian (SAS) AF: 0.00 AC: 0 AN: 83298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105356

Other (OTH) AF: 0.00 AC: 0 AN: 59546

⚠️ 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.: 35

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	Uncertain	0.35
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.4	L
PhyloP100		1.6
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.036	D
Polyphen		0.95	P
Vest4		0.46
MutPred		0.24		Loss of MoRF binding (P = 0.0152)
MVP		0.76
MPC		1.0
ClinPred		0.95	D
GERP RS		3.8
PromoterAI		0.057	Neutral
Varity_R		0.39
gMVP		0.20
Mutation Taster		=93/7	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: rs1404601896; hg19: chr9-25678090;