chr17-50863594-T-G

Variant names:

• chr17-50863594-T-G
• rs756855994
• NM_005749.4:c.424A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005749.4(TOB1):​c.424A>C​(p.Ile142Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I142V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TOB1 NM_005749.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.86
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3293608).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOB1	NM_005749.4	c.424A>C	p.Ile142Leu	missense_variant	Exon 2 of 2	ENST00000499247.3	NP_005740.1
TOB1	NM_001243877.2	c.424A>C	p.Ile142Leu	missense_variant	Exon 3 of 3		NP_001230806.1
TOB1	NM_001243885.2	c.7A>C	p.Ile3Leu	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.424A>C	p.Ile142Leu	missense_variant	Exon 2 of 2	1	NM_005749.4	ENSP00000427695.1
TOB1	ENST00000268957.3	c.424A>C	p.Ile142Leu	missense_variant	Exon 3 of 3	1		ENSP00000268957.3
TOB1	ENST00000509385.1	n.664A>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 47

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.7	L;L
PhyloP100		4.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.15
Sift	Benign	0.059	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.90	P;P
Vest4		0.50
MutPred		0.18		Loss of glycosylation at S143 (P = 0.0725);Loss of glycosylation at S143 (P = 0.0725);
MVP		0.17
MPC		0.34
ClinPred		0.87	D
GERP RS		4.5
Varity_R		0.34
gMVP		0.32

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: rs756855994; hg19: chr17-48940955;