17-50863414-C-T

Variant names:

• chr17-50863414-C-T
• NM_005749.4:c.604G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005749.4(TOB1):​c.604G>A​(p.Ala202Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TOB1 NM_005749.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.77

Genes affected

TOB1 (HGNC:11979): (transducer of ERBB2, 1) This gene encodes a member of the transducer of erbB-2 /B-cell translocation gene protein family. Members of this family are anti-proliferative factors that have the potential to regulate cell growth. The encoded protein may function as a tumor suppressor. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12907478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOB1	NM_005749.4	c.604G>A	p.Ala202Thr	missense_variant	Exon 2 of 2	ENST00000499247.3	NP_005740.1
TOB1	NM_001243877.2	c.604G>A	p.Ala202Thr	missense_variant	Exon 3 of 3		NP_001230806.1
TOB1	NM_001243885.2	c.187G>A	p.Ala63Thr	missense_variant	Exon 2 of 2		NP_001230814.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOB1	ENST00000499247.3	c.604G>A	p.Ala202Thr	missense_variant	Exon 2 of 2	1	NM_005749.4	ENSP00000427695.1
TOB1	ENST00000268957.3	c.604G>A	p.Ala202Thr	missense_variant	Exon 3 of 3	1		ENSP00000268957.3
TOB1	ENST00000509385.1	n.844G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461890 Hom.: 0 Cov.: 49 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.604G>A (p.A202T) alteration is located in exon 2 (coding exon 1) of the TOB1 gene. This alteration results from a G to A substitution at nucleotide position 604, causing the alanine (A) at amino acid position 202 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	-0.044
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.75	N;N
REVEL	Benign	0.13
Sift	Benign	0.10	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.0010	B;B
Vest4		0.16
MutPred		0.33		Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);
MVP		0.12
MPC		0.30
ClinPred		0.42	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.040
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-48940775;