rs207482230

Positions:

• chr3-100748182-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_006070.6(TFG):​c.854C>T​(p.Pro285Leu) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TFG NM_006070.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.75

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-100748182-C-T is Pathogenic according to our data. Variant chr3-100748182-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39197457). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFG	NM_006070.6	c.854C>T	p.Pro285Leu	missense_variant	8/8	ENST00000240851.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFG	ENST00000240851.9	c.854C>T	p.Pro285Leu	missense_variant	8/8	1	NM_006070.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250522 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135498

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary motor and sensory neuropathy, Okinawa type Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Aug 18, 2015	This variant has been previously reported as disease-causing and was found in an individual with peripheral neuropathy. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2013	- -

Amyotrophic Lateral Sclerosis with Sensory Neuropathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

Mar 31, 2020

- -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Apr 05, 2019

ACMG classification criteria: PS3, PM2, PP1 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 29, 2016

The P285L missense variant in the TFG gene has been previously reported to segregate with proximal hereditary motor and sensory neuropathy (HMSN-P) in several large families (Lee et al., 2013, Ishiura et al., 2012, Alavi et al., 2015). Functional studies demonstrate the P285L disrupts the protein and leads to inclusion body formation in cultured cells (Ishiura et al., 2012). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P285L 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 in mammals. -

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

Jun 08, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TFG function (PMID: 22883144, 24613659, 28196470). 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: 37089). This missense change has been observed in individuals with hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) (PMID: 22883144, 23553329, 25725944). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs207482230, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 285 of the TFG protein (p.Pro285Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.0081	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	.;D;D;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	.;.;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.024	D;T;T;D
Polyphen		0.080	.;B;B;.
Vest4		0.75
MutPred		0.28		.;Loss of loop (P = 9e-04);Loss of loop (P = 9e-04);.;
MVP		0.73
MPC		0.38
ClinPred		0.53	D
GERP RS		6.2
Varity_R		0.068
gMVP		0.11

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: rs207482230; hg19: chr3-100467026;