chr12-57782818-C-G

Variant names:

• chr12-57782818-C-G
• rs372337739
• NM_005726.6:c.17C>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/21 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
• Publications: 0 publications found

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

ENSG00000257921 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSFM	NM_005726.6	c.17C>G	p.Ser6Trp	missense_variant	Exon 1 of 6	ENST00000652027.2	NP_005717.3
TSFM	NM_001172696.2	c.17C>G	p.Ser6Trp	missense_variant	Exon 1 of 7		NP_001166167.1
TSFM	NM_001172697.2	c.17C>G	p.Ser6Trp	missense_variant	Exon 1 of 6		NP_001166168.1
TSFM	NM_001172695.2	c.17C>G	p.Ser6Trp	missense_variant	Exon 1 of 5		NP_001166166.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSFM	ENST00000652027.2	c.17C>G	p.Ser6Trp	missense_variant	Exon 1 of 6		NM_005726.6	ENSP00000499171.2
ENSG00000257921	ENST00000546504.1	c.77-292C>G		intron_variant	Intron 1 of 3	2		ENSP00000449544.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33006

American (AMR) AF: 0.00 AC: 0 AN: 41736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25718

East Asian (EAS) AF: 0.00 AC: 0 AN: 38476

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103092

Other (OTH) AF: 0.00 AC: 0 AN: 59576

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		1.9
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
PromoterAI		-0.042	Neutral
Varity_R		0.11
gMVP		0.55
Mutation Taster		=80/20	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: rs372337739; hg19: chr12-58176601;