chr3-100744825-G-T

Variant names:

• chr3-100744825-G-T
• rs41272979
• NM_006070.6:c.722-8G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006070.6(TFG):​c.722-8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00936 in 1,598,458 control chromosomes in the GnomAD database, including 329 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (184 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (145 hom.)
• Consequence: TFG NM_006070.6 splice_region, intron
• Scores: Splicing: ADA: 0.000007947
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.23
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 3-100744825-G-T is Benign according to our data. Variant chr3-100744825-G-T is described in ClinVar as Benign. ClinVar VariationId is 378722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0896 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.722-8G>T		splice_region intron	N/A	NP_006061.2
	TFG	NM_001007565.2		c.722-8G>T		splice_region intron	N/A	NP_001007566.1
	TFG	NM_001195478.2		c.722-8G>T		splice_region intron	N/A	NP_001182407.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFG	ENST00000240851.9	TSL:1 MANE Select	c.722-8G>T		splice_region intron	N/A	ENSP00000240851.4
	TFG	ENST00000476228.5	TSL:1	c.710-8G>T		splice_region intron	N/A	ENSP00000417952.1
	TFG	ENST00000615993.2	TSL:1	c.710-8G>T		splice_region intron	N/A	ENSP00000479269.2

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 4513 AN: 152004 Hom.: 183 Cov.: 32

Gnomad AFR AF: 0.0920

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00651

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00531

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0111 AC: 2769 AN: 248642 AF XY: 0.00927

Gnomad AFR exome AF: 0.0983

Gnomad AMR exome AF: 0.00659

Gnomad ASJ exome AF: 0.000601

Gnomad EAS exome AF: 0.00215

Gnomad FIN exome AF: 0.00847

Gnomad NFE exome AF: 0.00534

Gnomad OTH exome AF: 0.00766

GnomAD4 exome AF: 0.00722 AC: 10440 AN: 1446336 Hom.: 145 Cov.: 29 AF XY: 0.00678 AC XY: 4883 AN XY: 720242

African (AFR) AF: 0.0918 AC: 3031 AN: 33024

American (AMR) AF: 0.00797 AC: 353 AN: 44318

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 25970

East Asian (EAS) AF: 0.00114 AC: 45 AN: 39516

South Asian (SAS) AF: 0.00252 AC: 215 AN: 85380

European-Finnish (FIN) AF: 0.00829 AC: 442 AN: 53330

Middle Eastern (MID) AF: 0.00698 AC: 40 AN: 5728

European-Non Finnish (NFE) AF: 0.00517 AC: 5679 AN: 1099250

Other (OTH) AF: 0.0100 AC: 598 AN: 59820

GnomAD4 genome AF: 0.0297 AC: 4524 AN: 152122 Hom.: 184 Cov.: 32 AF XY: 0.0287 AC XY: 2138 AN XY: 74382

African (AFR) AF: 0.0920 AC: 3815 AN: 41466

American (AMR) AF: 0.0136 AC: 208 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5176

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4822

European-Finnish (FIN) AF: 0.00651 AC: 69 AN: 10598

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

European-Non Finnish (NFE) AF: 0.00531 AC: 361 AN: 67986

Other (OTH) AF: 0.0199 AC: 42 AN: 2110

Alfa AF: 0.0140 Hom.: 46

Bravo AF: 0.0351

Asia WGS AF: 0.00462 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 30, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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	-0.91
CADD	Benign	0.17
DANN	Benign	0.48
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000079
dbscSNV1_RF	Benign	0.0080
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: rs41272979; hg19: chr3-100463669;