rs111356679

chr3-100748388-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_006070.6(TFG):c.1060C>G(p.Pro354Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,614,138 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (8 hom.)
• Consequence: TFG NM_006070.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.608

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009718746).
• BP6: Variant 3-100748388-C-G is Benign according to our data. Variant chr3-100748388-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 245772.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0012 (183/152308) while in subpopulation AMR AF= 0.00209 (32/15302). AF 95% confidence interval is 0.00152. There are 1 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFG	NM_006070.6	c.1060C>G	p.Pro354Ala	missense_variant	8/8	ENST00000240851.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFG	ENST00000240851.9	c.1060C>G	p.Pro354Ala	missense_variant	8/8	1	NM_006070.6	P4

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 182 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00123 AC: 309 AN: 251136 Hom.: 1 AF XY: 0.00136 AC XY: 184 AN XY: 135706

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000984

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00197

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00132 AC: 1927 AN: 1461830 Hom.: 8 Cov.: 33 AF XY: 0.00132 AC XY: 960 AN XY: 727214

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000580

Gnomad4 FIN exome AF: 0.000655

Gnomad4 NFE exome AF: 0.00147

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152308 Hom.: 1 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74476

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00173

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00146 Hom.: 1

Bravo AF: 0.00125

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00133 AC: 162

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00290

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TFG: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 11, 2017

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 18, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary motor and sensory neuropathy, Okinawa type;C3714897:Hereditary spastic paraplegia 57 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.085
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0097	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.90	N;N;N;N
REVEL	Benign	0.047
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		0.0010	.;B;B;.
Vest4		0.082
MVP		0.33
MPC		0.74
ClinPred		0.087	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs111356679; hg19: chr3-100467232;