NM_006070.6:c.980A>C

Variant names:

• chr3-100748308-A-C
• rs1431898500
• NM_006070.6:c.980A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006070.6(TFG):​c.980A>C​(p.Gln327Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q327R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TFG NM_006070.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.38
• 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: 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFG	NM_006070.6	c.980A>C	p.Gln327Pro	missense_variant	Exon 8 of 8	ENST00000240851.9	NP_006061.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFG	ENST00000240851.9	c.980A>C	p.Gln327Pro	missense_variant	Exon 8 of 8	1	NM_006070.6	ENSP00000240851.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	.;T;T;.
Eigen	Benign	-0.047
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	.;.;T;T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	.;M;M;.
PhyloP100		8.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.13	N;N;N;N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.61
MutPred		0.31		.;Gain of glycosylation at Y329 (P = 0.0078);Gain of glycosylation at Y329 (P = 0.0078);.;
MVP		0.50
MPC		0.56
ClinPred		0.78	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.33
gMVP		0.49
Mutation Taster		=43/57	disease causing

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: rs1431898500; hg19: chr3-100467152;