Genetic Variant NM_006070.6:c.552G>A (chr3-100732644-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006070.6(TFG):c.552G>A(p.Ala184Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00946 in 1,611,108 control chromosomes in the GnomAD database, including 389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A184A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.030 ( 184 hom., cov: 32)

Exomes 𝑓: 0.0073 ( 205 hom. )

Consequence

TFG
NM_006070.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.740

Publications

2 publications found

Variant links:

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

TFG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 3-100732644-G-A is Benign according to our data. Variant chr3-100732644-G-A is described in ClinVar as Benign. ClinVar VariationId is 378720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.74 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0899 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TFG	NM_006070.6	MANE Select	c.552G>A	p.Ala184Ala	synonymous	Exon 5 of 8	NP_006061.2
TFG	NM_001007565.2		c.552G>A	p.Ala184Ala	synonymous	Exon 5 of 8	NP_001007566.1	Q92734-1
TFG	NM_001195478.2		c.552G>A	p.Ala184Ala	synonymous	Exon 5 of 8	NP_001182407.1	Q92734-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TFG	ENST00000240851.9	TSL:1 MANE Select	c.552G>A	p.Ala184Ala	synonymous	Exon 5 of 8	ENSP00000240851.4	Q92734-1
TFG	ENST00000476228.5	TSL:1	c.552G>A	p.Ala184Ala	synonymous	Exon 5 of 8	ENSP00000417952.1	Q92734-2
TFG	ENST00000615993.2	TSL:1	c.552G>A	p.Ala184Ala	synonymous	Exon 5 of 9	ENSP00000479269.2	Q92734-4

Frequencies

GnomAD3 genomes

AF:

0.0298

AC:

4537

AN:

152126

Hom.:

183

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0924

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0136

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00670

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00532

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.0112

AC:

2789

AN:

248312

AF XY:

0.00936

show subpopulations

Gnomad AFR exome

AF:

0.0993

Gnomad AMR exome

AF:

0.00682

Gnomad ASJ exome

AF:

0.000599

Gnomad EAS exome

AF:

0.00214

Gnomad FIN exome

AF:

0.00849

Gnomad NFE exome

AF:

0.00538

Gnomad OTH exome

AF:

0.00779

GnomAD4 exome

AF:

0.00733

AC:

10690

AN:

1458864

Hom.:

205

Cov.:

AF XY:

0.00690

AC XY:

5005

AN XY:

725770

show subpopulations

African (AFR)

AF:

0.0946

AC:

3148

AN:

33284

American (AMR)

AF:

0.00811

AC:

359

AN:

44274

Ashkenazi Jewish (ASJ)

AF:

0.00142

AC:

AN:

26056

East Asian (EAS)

AF:

0.00119

AC:

AN:

39438

South Asian (SAS)

AF:

0.00257

AC:

221

AN:

85826

European-Finnish (FIN)

AF:

0.00838

AC:

447

AN:

53336

Middle Eastern (MID)

AF:

0.00714

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00520

AC:

5779

AN:

1110654

Other (OTH)

AF:

0.0101

AC:

611

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

453

906

1360

1813

2266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

266

532

798

1064

1330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0299

AC:

4548

AN:

152244

Hom.:

184

Cov.:

AF XY:

0.0288

AC XY:

2145

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0924

AC:

3836

AN:

41534

American (AMR)

AF:

0.0136

AC:

208

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3466

East Asian (EAS)

AF:

0.00174

AC:

AN:

5182

South Asian (SAS)

AF:

0.00290

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00670

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00532

AC:

362

AN:

68020

Other (OTH)

AF:

0.0199

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

209

419

628

838

1047

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0140

Hom.:

Bravo

AF:

0.0352

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00533

EpiControl

AF:

0.00514

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

2.8

(source)

DANN

Benign

0.69

PhyloP100

-0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over