rs770053266

chr3-100728834-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006070.6(TFG):c.391C>T(p.Pro131Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,453,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TFG NM_006070.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.44

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10872474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFG	NM_006070.6	c.391C>T	p.Pro131Ser	missense_variant	4/8	ENST00000240851.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFG	ENST00000240851.9	c.391C>T	p.Pro131Ser	missense_variant	4/8	1	NM_006070.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000165 AC: 4 AN: 242694 Hom.: 0 AF XY: 0.0000228 AC XY: 3 AN XY: 131512

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000228

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1453464 Hom.: 0 Cov.: 30 AF XY: 0.00000415 AC XY: 3 AN XY: 723176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000767

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary motor and sensory neuropathy, Okinawa type;C3714897:Hereditary spastic paraplegia 57 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TFG protein function. ClinVar contains an entry for this variant (Variation ID: 466408). This variant has not been reported in the literature in individuals affected with TFG-related conditions. This variant is present in population databases (rs770053266, gnomAD 0.02%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 131 of the TFG protein (p.Pro131Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	20
Dann	Pathogenic	1.0
Eigen	Benign	-0.086
Eigen_PC	Benign	0.087
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L;L;L;.;.;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.43	T
Sift4G	Benign	0.62	T;T;T;T;T;T;T;T
Polyphen		0.089	.;.;B;B;.;.;.;.
Vest4		0.23
MutPred		0.18		Loss of glycosylation at P126 (P = 0.0134);Loss of glycosylation at P126 (P = 0.0134);Loss of glycosylation at P126 (P = 0.0134);Loss of glycosylation at P126 (P = 0.0134);Loss of glycosylation at P126 (P = 0.0134);Loss of glycosylation at P126 (P = 0.0134);Loss of glycosylation at P126 (P = 0.0134);Loss of glycosylation at P126 (P = 0.0134);
MVP		0.35
MPC		0.39
ClinPred		0.16	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.33

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: rs770053266; hg19: chr3-100447678;