Genetic Variant TSFM:c.231+1096A>G (chr12-57784379-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005726.6(TSFM):c.231+1096A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 152,112 control chromosomes in the GnomAD database, including 8,788 homozygotes. 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: 𝑓 0.33 ( 8788 hom., cov: 32)

Consequence

TSFM
NM_005726.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.83

Publications

25 publications found

Variant links:

Genes affected

TSFM (HGNC:12367): (Ts translation elongation factor, mitochondrial) This gene encodes a mitochondrial translation elongation factor. The encoded protein is an enzyme that catalyzes the exchange of guanine nucleotides on the translation elongation factor Tu during the elongation step of mitchondrial protein translation. Mutations in this gene are associated with combined oxidative phosphorylation deficiency-3 syndrome. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2010]

TSFM Gene-Disease associations (from GenCC):

fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

TSFM links:

ENSG00000257921 (HGNC:):

ENSG00000257921 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.08).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
TSFM	NM_005726.6 link	c.231+1096A>G	intron_variant	Intron 2 of 5	ENST00000652027.2	NP_005717.3
TSFM	NM_001172696.2 link	c.231+1096A>G	intron_variant	Intron 2 of 6		NP_001166167.1
TSFM	NM_001172697.2 link	c.231+1096A>G	intron_variant	Intron 2 of 5		NP_001166168.1
TSFM	NM_001172695.2 link	c.231+1096A>G	intron_variant	Intron 2 of 4		NP_001166166.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSFM	ENST00000652027.2 link	c.231+1096A>G		intron_variant	Intron 2 of 5		NM_005726.6	ENSP00000499171.2
ENSG00000257921	ENST00000546504.1 link	c.288+727A>G		intron_variant	Intron 3 of 3	2		ENSP00000449544.1

Frequencies

GnomAD3 genomes

AF:

0.330

AC:

50123

AN:

151994

Hom.:

8761

Cov.:

show subpopulations

Gnomad AFR

AF:

0.288

Gnomad AMI

AF:

0.385

Gnomad AMR

AF:

0.283

Gnomad ASJ

AF:

0.297

Gnomad EAS

AF:

0.655

Gnomad SAS

AF:

0.567

Gnomad FIN

AF:

0.377

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.320

Gnomad OTH

AF:

0.283

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.330

AC:

50203

AN:

152112

Hom.:

8788

Cov.:

AF XY:

0.338

AC XY:

25135

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.289

AC:

11992

AN:

41494

American (AMR)

AF:

0.283

AC:

4328

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.297

AC:

1031

AN:

3466

East Asian (EAS)

AF:

0.655

AC:

3391

AN:

5178

South Asian (SAS)

AF:

0.567

AC:

2736

AN:

4822

European-Finnish (FIN)

AF:

0.377

AC:

3984

AN:

10566

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.320

AC:

21731

AN:

67972

Other (OTH)

AF:

0.289

AC:

611

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1713

3427

5140

6854

8567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

518

1036

1554

2072

2590

<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:

0.313

Hom.:

17752

Bravo

AF:

0.318

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.1

CADD

Benign

1.0

(source)

DANN

Benign

0.18

PhyloP100

-1.8

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over