3-100720048-G-T

Variant names:

• chr3-100720048-G-T
• rs150620449
• NM_006070.6:c.258G>T
• TFG p.Leu86Leu

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_006070.6(TFG):​c.258G>T​(p.Leu86Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,553,050 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L86L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: TFG NM_006070.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.81
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hereditary motor and sensory neuropathy, Okinawa type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
• hereditary spastic paraplegia 57

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
• autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 3-100720048-G-T is Benign according to our data. Variant chr3-100720048-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 386659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006070.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFG	NM_006070.6	MANE Select	c.258G>T	p.Leu86Leu	synonymous	Exon 3 of 8	NP_006061.2
	TFG	NM_001007565.2		c.258G>T	p.Leu86Leu	synonymous	Exon 3 of 8	NP_001007566.1	Q92734-1
	TFG	NM_001195478.2		c.258G>T	p.Leu86Leu	synonymous	Exon 3 of 8	NP_001182407.1	Q92734-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFG	ENST00000240851.9	TSL:1 MANE Select	c.258G>T	p.Leu86Leu	synonymous	Exon 3 of 8	ENSP00000240851.4	Q92734-1
	TFG	ENST00000476228.5	TSL:1	c.258G>T	p.Leu86Leu	synonymous	Exon 3 of 8	ENSP00000417952.1	Q92734-2
	TFG	ENST00000615993.2	TSL:1	c.258G>T	p.Leu86Leu	synonymous	Exon 3 of 9	ENSP00000479269.2	Q92734-4

Frequencies

GnomAD3 genomes AF: 0.000876 AC: 133 AN: 151810 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.000932 AC: 198 AN: 212410 AF XY: 0.00100

Gnomad AFR exome AF: 0.000430

Gnomad AMR exome AF: 0.000205

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000190

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.000823

GnomAD4 exome AF: 0.00139 AC: 1943 AN: 1401122 Hom.: 1 Cov.: 24 AF XY: 0.00128 AC XY: 895 AN XY: 697544

African (AFR) AF: 0.000231 AC: 7 AN: 30352

American (AMR) AF: 0.000422 AC: 15 AN: 35522

Ashkenazi Jewish (ASJ) AF: 0.000121 AC: 3 AN: 24806

East Asian (EAS) AF: 0.00 AC: 0 AN: 37378

South Asian (SAS) AF: 0.00 AC: 0 AN: 76194

European-Finnish (FIN) AF: 0.000265 AC: 14 AN: 52812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 0.00170 AC: 1838 AN: 1080628

Other (OTH) AF: 0.00114 AC: 66 AN: 57900

GnomAD4 genome AF: 0.000875 AC: 133 AN: 151928 Hom.: 0 Cov.: 33 AF XY: 0.000889 AC XY: 66 AN XY: 74248

African (AFR) AF: 0.000338 AC: 14 AN: 41458

American (AMR) AF: 0.00118 AC: 18 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000191 AC: 2 AN: 10482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00134 AC: 91 AN: 67950

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00111 Hom.: 1

Bravo AF: 0.00101

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	Hereditary motor and sensory neuropathy, Okinawa type;C3714897:Hereditary spastic paraplegia 57 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	TFG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.3
DANN	Benign	0.78
PhyloP100		1.8
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs150620449; hg19: chr3-100438892;