3-100709467-AT-A

Variant names:

• chr3-100709467-AT-A
• rs561497809
• ENST00000675692.1:c.-287delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001007565.2(TFG):​c.-44+47delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0311 in 148,022 control chromosomes in the GnomAD database, including 184 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.031 (184 hom., cov: 32)
  • Exomes 𝑓: 0.058 (0 hom.)
• Consequence: TFG NM_001007565.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.942
• 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.

• BP6: Variant 3-100709467-AT-A is Benign according to our data. Variant chr3-100709467-AT-A is described in ClinVar as Benign. ClinVar VariationId is 1280370.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0916 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001007565.2. 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_001007565.2		c.-44+47delT		intron	N/A	NP_001007566.1	Q92734-1
	TFG	NM_006070.6	MANE Select	c.-297delT		upstream_gene	N/A	NP_006061.2
	TFG	NM_001195478.2		c.-164delT		upstream_gene	N/A	NP_001182407.1	Q92734-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFG	ENST00000675692.1		c.-287delT		5_prime_UTR	Exon 1 of 9	ENSP00000502034.1	A0A6Q8PFY7
	TFG	ENST00000674615.1		c.-385delT		5_prime_UTR	Exon 1 of 9	ENSP00000502734.1	Q92734-1
	TFG	ENST00000675553.1		c.-154delT		5_prime_UTR	Exon 1 of 8	ENSP00000501815.1	Q92734-1

Frequencies

GnomAD3 genomes AF: 0.0309 AC: 4568 AN: 147692 Hom.: 183 Cov.: 32

Gnomad AFR AF: 0.0939

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.00582

Gnomad EAS AF: 0.00178

Gnomad SAS AF: 0.00296

Gnomad FIN AF: 0.00786

Gnomad MID AF: 0.00993

Gnomad NFE AF: 0.00576

Gnomad OTH AF: 0.0221

GnomAD4 exome AF: 0.0578 AC: 17 AN: 294 Hom.: 0 Cov.: 0 AF XY: 0.0541 AC XY: 12 AN XY: 222

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 12

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.125 AC: 2 AN: 16

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0591 AC: 15 AN: 254

Other (OTH) AF: 0.00 AC: 0 AN: 6

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0310 AC: 4580 AN: 147728 Hom.: 184 Cov.: 32 AF XY: 0.0300 AC XY: 2156 AN XY: 71866

African (AFR) AF: 0.0941 AC: 3819 AN: 40604

American (AMR) AF: 0.0143 AC: 212 AN: 14866

Ashkenazi Jewish (ASJ) AF: 0.00582 AC: 20 AN: 3436

East Asian (EAS) AF: 0.00179 AC: 9 AN: 5042

South Asian (SAS) AF: 0.00298 AC: 14 AN: 4704

European-Finnish (FIN) AF: 0.00786 AC: 72 AN: 9158

Middle Eastern (MID) AF: 0.0109 AC: 3 AN: 276

European-Non Finnish (NFE) AF: 0.00576 AC: 384 AN: 66684

Other (OTH) AF: 0.0220 AC: 45 AN: 2048

Alfa AF: 0.00264 Hom.: 0

Bravo AF: 0.0354

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.94
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs561497809; hg19: chr3-100428311; COSMIC: COSV53749916; COSMIC: COSV53749916;