3-100732499-T-A

Variant names:

• chr3-100732499-T-A
• rs115896544
• NM_006070.6:c.416-9T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006070.6(TFG):​c.416-9T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TFG NM_006070.6 intron
• Scores: Splicing: ADA: 0.0007376
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.485
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFG	NM_006070.6	c.416-9T>A		intron_variant	Intron 4 of 7	ENST00000240851.9	NP_006061.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFG	ENST00000240851.9	c.416-9T>A		intron_variant	Intron 4 of 7	1	NM_006070.6	ENSP00000240851.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000428 AC: 1 AN: 233520 AF XY: 0.00

Gnomad AFR exome AF: 0.0000633

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443072 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 717820

African (AFR) AF: 0.0000312 AC: 1 AN: 32004

American (AMR) AF: 0.00 AC: 0 AN: 39436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25162

East Asian (EAS) AF: 0.00 AC: 0 AN: 39460

South Asian (SAS) AF: 0.00 AC: 0 AN: 82686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5392

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106396

Other (OTH) AF: 0.00 AC: 0 AN: 59454

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 13

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.3
DANN	Benign	0.78
PhyloP100		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00074
dbscSNV1_RF	Benign	0.14
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: rs115896544; hg19: chr3-100451343;