3-100728759-C-T

Position:

chr3-100728759-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_006070.6(TFG):c.316C>T(p.Arg106Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000292 in 1,611,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R106H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

TFG
NM_006070.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.31

Variant links:

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]

TFG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a coiled_coil_region (size 27) in uniprot entity TFG_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006070.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.844

PP5

Variant 3-100728759-C-T is Pathogenic according to our data. Variant chr3-100728759-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 100909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-100728759-C-T is described in Lovd as [Pathogenic]. Variant chr3-100728759-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFG	NM_006070.6 linkuse as main transcript	c.316C>T	p.Arg106Cys	missense_variant	4/8	ENST00000240851.9	NP_006061.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFG	ENST00000240851.9 linkuse as main transcript	c.316C>T	p.Arg106Cys	missense_variant	4/8	1	NM_006070.6	ENSP00000240851	P4	Q92734-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000401

AC:

AN:

249380

Hom.:

AF XY:

0.0000519

AC XY:

AN XY:

134908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1459512

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726102

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00918

Hom.:

235

Bravo

AF:

0.00000378

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000550

EpiControl

AF:

0.000179

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	May 10, 2022	DNA sequence analysis of the TGF gene demonstrated a sequence change, c.316C>T, in exon 4 that results in an amino acid change, p.Arg106Cys. The p.Arg106Cys change affects a highly conserved amino acid residue located in a domain of the TFG protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg106Cys substitution. This sequence change has been described in the gnomAD database with a frequency of 0.0086% in the non-Finnish European subpopulation (dbSNP rs587777175). This pathogenic sequence change has previously been described in the homozygous state in individuals with autosomal recessive spastic paraplegia (PMID: 23479643, 27492651, 29971521). Heterozygous pathogenic variants have also been described in individuals with autosomal dominant hereditary motor and sensory neuropathy (PMID: 22883144). However, variants associated with autosomal dominant conditions appear to be located in a different region of the protein than the p.Arg106Cys substitution (PMID: 26945032). Heterozygous carriers of the p.Arg106Cys change have not been reported to be affected. The TGF cDNA reference sequence used is NM_006070.5 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2021	Published functional studies demonstrate damaging effects on protein secretion from the endoplasmic reticulum (ER), ER morphology, and mitochondrial dysfunction (Beetz et al., 2013; Harlalka et al., 2016; Slosarek et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 32488467, 30157421, 30221345, 26945032, 24954637, 27813252, 25098539, 24613659, 27601211, 27492651, 29971521, 23479643) -

Hereditary spastic paraplegia 57

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 26, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Oct 05, 2021	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2020

The p.R106C variant (also known as c.316C>T), located in coding exon 3 of the TFG gene, results from a C to T substitution at nucleotide position 316. The arginine at codon 106 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in the homozygous state in multiple unrelated families and segregates with autosomal recessive hereditary spastic paraplegia and optic nerve hypoplasia in affected relatives (Beetz C et al. Proc Natl Acad Sci U S A, 2013 Mar;110:5091-6; Harlalka GV et al. Hum Mutat, 2016 11;37:1157-1161; Kvarnung M et al. Clin Genet, 2018 12;94:528-537; Catania A et al. Neurogenetics, 2018 08;19:179-187). Functional studies with this alteration show impaired TFG protein oligomerization leading to abnormal ER function (Beetz C et al. Proc Natl Acad Sci U S A, 2013 Mar;110:5091-6; Harlalka GV et al. Hum Mutat, 2016 11;37:1157-1161; Slosarek EL et al. Cell Rep, 2018 08;24:2248-2260). Based on the supporting evidence, this variant is pathogenic for spastic paraplegia 57 (SPG57); however, the clinical significance for hereditary motor and sensory neuropathy, Okinawa type (HMSN-P) is unclear. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TFG function (PMID: 23479643, 27492651, 30157421). 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: 100909). This missense change has been observed in individuals with autosomal recessive hereditary spastic paraplegia (PMID: 23479643, 27492651, 29971521). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs587777175, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 106 of the TFG protein (p.Arg106Cys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

.;.;D;D;T;.;T;T;.

Eigen

Benign

0.081

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

.;.;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.4

M;M;M;M;.;M;.;.;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-5.6

.;D;D;D;D;D;D;D;.

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

.;D;D;D;D;D;D;D;.

Sift4G

Uncertain

0.0030

D;D;D;D;D;D;D;D;D

Polyphen

0.014

.;.;B;B;.;.;.;.;.

Vest4

0.92

MVP

0.86

MPC

1.3

ClinPred

0.76

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.72

gMVP

0.72

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over