3-100732644-G-A

Variant names:

• chr3-100732644-G-A
• rs35648279
• NM_006070.6:c.552G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006070.6(TFG):​c.552G>A​(p.Ala184Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00946 in 1,611,108 control chromosomes in the GnomAD database, including 389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A184A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.030 (184 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (205 hom.)
• Consequence: TFG NM_006070.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.740
• Publications: 2 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: Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary spastic paraplegia 57

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 3-100732644-G-A is Benign according to our data. Variant chr3-100732644-G-A is described in ClinVar as Benign. ClinVar VariationId is 378720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0899 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFG	NM_006070.6	MANE Select	c.552G>A	p.Ala184Ala	synonymous	Exon 5 of 8	NP_006061.2
	TFG	NM_001007565.2		c.552G>A	p.Ala184Ala	synonymous	Exon 5 of 8	NP_001007566.1
	TFG	NM_001195478.2		c.552G>A	p.Ala184Ala	synonymous	Exon 5 of 8	NP_001182407.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFG	ENST00000240851.9	TSL:1 MANE Select	c.552G>A	p.Ala184Ala	synonymous	Exon 5 of 8	ENSP00000240851.4
	TFG	ENST00000476228.5	TSL:1	c.552G>A	p.Ala184Ala	synonymous	Exon 5 of 8	ENSP00000417952.1
	TFG	ENST00000615993.2	TSL:1	c.552G>A	p.Ala184Ala	synonymous	Exon 5 of 9	ENSP00000479269.2

Frequencies

GnomAD3 genomes AF: 0.0298 AC: 4537 AN: 152126 Hom.: 183 Cov.: 32

Gnomad AFR AF: 0.0924

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00670

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00532

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0112 AC: 2789 AN: 248312 AF XY: 0.00936

Gnomad AFR exome AF: 0.0993

Gnomad AMR exome AF: 0.00682

Gnomad ASJ exome AF: 0.000599

Gnomad EAS exome AF: 0.00214

Gnomad FIN exome AF: 0.00849

Gnomad NFE exome AF: 0.00538

Gnomad OTH exome AF: 0.00779

GnomAD4 exome AF: 0.00733 AC: 10690 AN: 1458864 Hom.: 205 Cov.: 30 AF XY: 0.00690 AC XY: 5005 AN XY: 725770

African (AFR) AF: 0.0946 AC: 3148 AN: 33284

American (AMR) AF: 0.00811 AC: 359 AN: 44274

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26056

East Asian (EAS) AF: 0.00119 AC: 47 AN: 39438

South Asian (SAS) AF: 0.00257 AC: 221 AN: 85826

European-Finnish (FIN) AF: 0.00838 AC: 447 AN: 53336

Middle Eastern (MID) AF: 0.00714 AC: 41 AN: 5746

European-Non Finnish (NFE) AF: 0.00520 AC: 5779 AN: 1110654

Other (OTH) AF: 0.0101 AC: 611 AN: 60250

GnomAD4 genome AF: 0.0299 AC: 4548 AN: 152244 Hom.: 184 Cov.: 32 AF XY: 0.0288 AC XY: 2145 AN XY: 74438

African (AFR) AF: 0.0924 AC: 3836 AN: 41534

American (AMR) AF: 0.0136 AC: 208 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5182

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4826

European-Finnish (FIN) AF: 0.00670 AC: 71 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00532 AC: 362 AN: 68020

Other (OTH) AF: 0.0199 AC: 42 AN: 2108

Alfa AF: 0.0140 Hom.: 37

Bravo AF: 0.0352

Asia WGS AF: 0.00462 AC: 17 AN: 3478

EpiCase AF: 0.00533

EpiControl AF: 0.00514

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Oct 30, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Apr 17, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Hereditary motor and sensory neuropathy, Okinawa type;C3714897:Hereditary spastic paraplegia 57 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.8
DANN	Benign	0.69
PhyloP100		-0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35648279; hg19: chr3-100451488;