rs12562

Variant names:

• chr3-100736589-T-G
• rs12562
• NM_006070.6:c.594T>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_006070.6(TFG):​c.594T>G​(p.Ala198Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00651 in 1,613,938 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (34 hom.)
• Consequence: TFG NM_006070.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.57
• Publications: 4 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: 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

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 3-100736589-T-G is Benign according to our data. Variant chr3-100736589-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 466410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.57 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.594T>G	p.Ala198Ala	synonymous	Exon 6 of 8	NP_006061.2
	TFG	NM_001007565.2		c.594T>G	p.Ala198Ala	synonymous	Exon 6 of 8	NP_001007566.1	Q92734-1
	TFG	NM_001195478.2		c.594T>G	p.Ala198Ala	synonymous	Exon 6 of 8	NP_001182407.1	Q92734-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFG	ENST00000240851.9	TSL:1 MANE Select	c.594T>G	p.Ala198Ala	synonymous	Exon 6 of 8	ENSP00000240851.4	Q92734-1
	TFG	ENST00000476228.5	TSL:1	c.594T>G	p.Ala198Ala	synonymous	Exon 6 of 8	ENSP00000417952.1	Q92734-2
	TFG	ENST00000615993.2	TSL:1	c.594T>G	p.Ala198Ala	synonymous	Exon 6 of 9	ENSP00000479269.2	Q92734-4

Frequencies

GnomAD3 genomes AF: 0.00404 AC: 615 AN: 152130 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00716

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00442 AC: 1110 AN: 251178 AF XY: 0.00463

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00767

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00677 AC: 9899 AN: 1461690 Hom.: 34 Cov.: 31 AF XY: 0.00662 AC XY: 4817 AN XY: 727138

African (AFR) AF: 0.00114 AC: 38 AN: 33470

American (AMR) AF: 0.00148 AC: 66 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00367 AC: 96 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00211 AC: 182 AN: 86252

European-Finnish (FIN) AF: 0.00251 AC: 134 AN: 53416

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5758

European-Non Finnish (NFE) AF: 0.00808 AC: 8986 AN: 1111920

Other (OTH) AF: 0.00651 AC: 393 AN: 60388

GnomAD4 genome AF: 0.00404 AC: 615 AN: 152248 Hom.: 2 Cov.: 32 AF XY: 0.00340 AC XY: 253 AN XY: 74422

African (AFR) AF: 0.00128 AC: 53 AN: 41536

American (AMR) AF: 0.00170 AC: 26 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00716 AC: 487 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00668 Hom.: 0

Bravo AF: 0.00424

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00666

EpiControl AF: 0.00717

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Hereditary motor and sensory neuropathy, Okinawa type;C3714897:Hereditary spastic paraplegia 57 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	TFG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	10
DANN	Benign	0.64
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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: rs12562; hg19: chr3-100455433;