3-100713709-T-G

Position:

• chr3-100713709-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006070.6(TFG):​c.24T>G​(p.Ser8Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S8S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TFG NM_006070.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

Genes affected

TFG (HGNC:11758): (trafficking from ER to golgi regulator) There are several documented fusion oncoproteins encoded partially by this gene. This gene also participates in several oncogenic rearrangements resulting in anaplastic lymphoma and mixoid chondrosarcoma, and may play a role in the NF-kappaB pathway. Multiple transcript variants have been found for this gene. [provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39801735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFG	NM_006070.6	c.24T>G	p.Ser8Arg	missense_variant	2/8	ENST00000240851.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFG	ENST00000240851.9	c.24T>G	p.Ser8Arg	missense_variant	2/8	1	NM_006070.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 08, 2017

The S8R variant in the TFG gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S8R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S8R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret S8R as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	.;.;D;D;T;.;T;T;.
Eigen	Benign	-0.021
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	.;.;.;D;D;D;D;D;D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.8	L;L;L;L;.;L;.;.;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.4	.;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	.;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.020	D;D;D;D;T;D;D;D;D
Polyphen		1.0	.;.;D;D;.;.;.;.;.
Vest4		0.92
MutPred		0.25		Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);
MVP		0.87
MPC		1.2
ClinPred		0.97	D
GERP RS		2.3
Varity_R		0.61
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs1553699512; hg19: chr3-100432553;