NM_005749.4:c.962T>C

Variant names:

• chr17-50863056-A-G
• NM_005749.4:c.962T>C

Variant summary

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

The NM_005749.4(TOB1):​c.962T>C​(p.Phe321Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TOB1 NM_005749.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.85
• 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOB1	NM_005749.4	c.962T>C	p.Phe321Ser	missense_variant	Exon 2 of 2	ENST00000499247.3	NP_005740.1
TOB1	NM_001243877.2	c.962T>C	p.Phe321Ser	missense_variant	Exon 3 of 3		NP_001230806.1
TOB1	NM_001243885.2	c.545T>C	p.Phe182Ser	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.962T>C	p.Phe321Ser	missense_variant	Exon 2 of 2	1	NM_005749.4	ENSP00000427695.1
TOB1	ENST00000268957.3	c.962T>C	p.Phe321Ser	missense_variant	Exon 3 of 3	1		ENSP00000268957.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.962T>C (p.F321S) alteration is located in exon 2 (coding exon 1) of the TOB1 gene. This alteration results from a T to C substitution at nucleotide position 962, causing the phenylalanine (F) at amino acid position 321 to be replaced by a serine (S). 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	0.61
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;T
Eigen	Benign	0.036
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		8.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.076	B;B
Vest4		0.69
MutPred		0.67		Gain of disorder (P = 0.0058);Gain of disorder (P = 0.0058);
MVP		0.46
MPC		0.63
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.54
gMVP		0.65

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: chr17-48940417;