chr17-50863894-C-G

Variant names:

• chr17-50863894-C-G
• NM_005749.4:c.124G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005749.4(TOB1):​c.124G>C​(p.Gly42Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TOB1 NM_005749.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOB1	NM_005749.4	c.124G>C	p.Gly42Arg	missense_variant	Exon 2 of 2	ENST00000499247.3	NP_005740.1
TOB1	NM_001243877.2	c.124G>C	p.Gly42Arg	missense_variant	Exon 3 of 3		NP_001230806.1
TOB1	NM_001243885.2	c.-294G>C		5_prime_UTR_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.124G>C	p.Gly42Arg	missense_variant	Exon 2 of 2	1	NM_005749.4	ENSP00000427695.1
TOB1	ENST00000268957.3	c.124G>C	p.Gly42Arg	missense_variant	Exon 3 of 3	1		ENSP00000268957.3
TOB1	ENST00000509385.1	n.364G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 49

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.124G>C (p.G42R) alteration is located in exon 2 (coding exon 1) of the TOB1 gene. This alteration results from a G to C substitution at nucleotide position 124, causing the glycine (G) at amino acid position 42 to be replaced by an arginine (R). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.6	M;M
PhyloP100		7.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.0	D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.75
MutPred		0.67		Gain of MoRF binding (P = 0.0399);Gain of MoRF binding (P = 0.0399);
MVP		0.26
MPC		1.1
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.72

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

hg19: chr17-48941255;