3-100709616-G-C

Variant names:

• chr3-100709616-G-C
• rs1059363
• NM_006070.6:c.-149G>C

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.-149G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.672 in 150,804 control chromosomes in the GnomAD database, including 34,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34238 hom., cov: 26)
  • Exomes 𝑓: 0.64 (11 hom.)
• Consequence: TFG NM_006070.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.342
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Orphanet
• 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=-0.79).
• BP6: Variant 3-100709616-G-C is Benign according to our data. Variant chr3-100709616-G-C is described in ClinVar as Benign. ClinVar VariationId is 670587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.813 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFG	NM_006070.6	MANE Select	c.-149G>C		5_prime_UTR	Exon 1 of 8	NP_006061.2
	TFG	NM_001195479.2		c.-149G>C		5_prime_UTR	Exon 1 of 8	NP_001182408.1	Q92734-2
	TFG	NM_001007565.2		c.-44+185G>C		intron	N/A	NP_001007566.1	Q92734-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFG	ENST00000240851.9	TSL:1 MANE Select	c.-149G>C		5_prime_UTR	Exon 1 of 8	ENSP00000240851.4	Q92734-1
	TFG	ENST00000476228.5	TSL:1	c.-149G>C		5_prime_UTR	Exon 1 of 8	ENSP00000417952.1	Q92734-2
	TFG	ENST00000675692.1		c.-149G>C		5_prime_UTR	Exon 1 of 9	ENSP00000502034.1	A0A6Q8PFY7

Frequencies

GnomAD3 genomes AF: 0.672 AC: 101210 AN: 150648 Hom.: 34191 Cov.: 26

Gnomad AFR AF: 0.652

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.596

Gnomad EAS AF: 0.637

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.702

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.662

GnomAD4 exome AF: 0.640 AC: 32 AN: 50 Hom.: 11 Cov.: 0 AF XY: 0.667 AC XY: 20 AN XY: 30

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

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

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.667 AC: 32 AN: 48

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.672 AC: 101317 AN: 150754 Hom.: 34238 Cov.: 26 AF XY: 0.675 AC XY: 49695 AN XY: 73616

African (AFR) AF: 0.653 AC: 26786 AN: 41028

American (AMR) AF: 0.756 AC: 11499 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 2063 AN: 3460

East Asian (EAS) AF: 0.637 AC: 3164 AN: 4970

South Asian (SAS) AF: 0.835 AC: 3995 AN: 4784

European-Finnish (FIN) AF: 0.672 AC: 6987 AN: 10390

Middle Eastern (MID) AF: 0.702 AC: 205 AN: 292

European-Non Finnish (NFE) AF: 0.661 AC: 44661 AN: 67608

Other (OTH) AF: 0.666 AC: 1402 AN: 2104

Alfa AF: 0.674 Hom.: 4299

Bravo AF: 0.672

Asia WGS AF: 0.774 AC: 2684 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.5
DANN	Benign	0.71
PhyloP100		-0.34
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs1059363; hg19: chr3-100428460;