3-100732499-T-C

Position:

• chr3-100732499-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006070.6(TFG):​c.416-9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,595,378 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (57 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (59 hom.)
• Consequence: TFG NM_006070.6 intron
• Scores: Splicing: ADA: 0.0001047
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.485

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 3-100732499-T-C is Benign according to our data. Variant chr3-100732499-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 378719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFG	NM_006070.6	c.416-9T>C		intron_variant		ENST00000240851.9	NP_006061.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFG	ENST00000240851.9	c.416-9T>C		intron_variant		1	NM_006070.6	ENSP00000240851.4

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2382 AN: 152206 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0553

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00403 AC: 940 AN: 233520 Hom.: 28 AF XY: 0.00283 AC XY: 358 AN XY: 126500

Gnomad AFR exome AF: 0.0545

Gnomad AMR exome AF: 0.00212

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000747

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00155 AC: 2240 AN: 1443054 Hom.: 59 Cov.: 30 AF XY: 0.00133 AC XY: 953 AN XY: 717804

Gnomad4 AFR exome AF: 0.0570

Gnomad4 AMR exome AF: 0.00243

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000169

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000678

Gnomad4 OTH exome AF: 0.00353

GnomAD4 genome AF: 0.0157 AC: 2392 AN: 152324 Hom.: 57 Cov.: 32 AF XY: 0.0152 AC XY: 1130 AN XY: 74482

Gnomad4 AFR AF: 0.0554

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00487 Hom.: 5

Bravo AF: 0.0178

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary motor and sensory neuropathy, Okinawa type;C3714897:Hereditary spastic paraplegia 57 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 06, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 22, 2015

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. -

TFG-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.2
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.0040
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: rs115896544; hg19: chr3-100451343;