12-57782818-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005726.6(TSFM):c.17C>G(p.Ser6Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,572 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S6L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TSFM NM_005726.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSFM	NM_005726.6	c.17C>G	p.Ser6Trp	missense_variant	1/6	ENST00000652027.2
TSFM	NM_001172696.2	c.17C>G	p.Ser6Trp	missense_variant	1/7
TSFM	NM_001172697.2	c.17C>G	p.Ser6Trp	missense_variant	1/6
TSFM	NM_001172695.2	c.17C>G	p.Ser6Trp	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSFM	ENST00000652027.2	c.17C>G	p.Ser6Trp	missense_variant	1/6		NM_005726.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441572 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 715294

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 07, 2022

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 6 of the TSFM protein (p.Ser6Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSFM-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.16	T;.;.;.;T;.
Eigen	Benign	-0.080
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.52	D;D;D;D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.8	L;L;L;.;.;L
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		0.98	D;.;D;.;.;.
Vest4		0.53
MutPred		0.44		Loss of disorder (P = 0);Loss of disorder (P = 0);Loss of disorder (P = 0);Loss of disorder (P = 0);Loss of disorder (P = 0);Loss of disorder (P = 0);
MVP		0.72
MPC		0.37
ClinPred		0.93	D
GERP RS		5.0
Varity_R		0.11
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-58176601;