17-50863435-T-C

Variant names:

• chr17-50863435-T-C
• rs1972247231
• NM_005749.4:c.583A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005749.4(TOB1):​c.583A>G​(p.Ser195Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,894 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: 0.000010 (0 hom.)
• Consequence: TOB1 NM_005749.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13379404).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOB1	NM_005749.4	c.583A>G	p.Ser195Gly	missense_variant	Exon 2 of 2	ENST00000499247.3	NP_005740.1
TOB1	NM_001243877.2	c.583A>G	p.Ser195Gly	missense_variant	Exon 3 of 3		NP_001230806.1
TOB1	NM_001243885.2	c.166A>G	p.Ser56Gly	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.583A>G	p.Ser195Gly	missense_variant	Exon 2 of 2	1	NM_005749.4	ENSP00000427695.1
TOB1	ENST00000268957.3	c.583A>G	p.Ser195Gly	missense_variant	Exon 3 of 3	1		ENSP00000268957.3
TOB1	ENST00000509385.1	n.823A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461894 Hom.: 0 Cov.: 49 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

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: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.583A>G (p.S195G) alteration is located in exon 2 (coding exon 1) of the TOB1 gene. This alteration results from a A to G substitution at nucleotide position 583, causing the serine (S) at amino acid position 195 to be replaced by a glycine (G). 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	0.063
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.070
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	.;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.097
Sift	Benign	0.64	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.0	B;B
Vest4		0.35
MutPred		0.25		Loss of glycosylation at S195 (P = 0.0123);Loss of glycosylation at S195 (P = 0.0123);
MVP		0.093
MPC		0.29
ClinPred		0.35	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1972247231; hg19: chr17-48940796;