3-158645674-A-T

Variant names:

• chr3-158645674-A-T
• rs35942089
• NM_024996.7:c.127A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024996.7(GFM1):​c.127A>T​(p.Asn43Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N43D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFM1 NM_024996.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.87
• Publications: 0 publications found

Genes affected

GFM1 (HGNC:13780): (G elongation factor mitochondrial 1) Eukaryotes contain two protein translational systems, one in the cytoplasm and one in the mitochondria. Mitochondrial translation is crucial for maintaining mitochondrial function and mutations in this system lead to a breakdown in the respiratory chain-oxidative phosphorylation system and to impaired maintenance of mitochondrial DNA. This gene encodes one of the mitochondrial translation elongation factors. Its role in the regulation of normal mitochondrial function and in different disease states attributed to mitochondrial dysfunction is not known. [provided by RefSeq, Jul 2008]

LXN (HGNC:13347): (latexin) This gene encodes the only known protein inhibitor of zinc-dependent metallocarboxypeptidases. The encoded protein, latexin, downregulates the population size of hematopoietic stem cells. This protein is found to be downregulated in cancer cells because of promoter hypermethylation. [provided by RefSeq, Jul 2020]

ACMG classification

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024996.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFM1	NM_024996.7	MANE Select	c.127A>T	p.Asn43Tyr	missense	Exon 2 of 18	NP_079272.4
	GFM1	NM_001308164.2		c.127A>T	p.Asn43Tyr	missense	Exon 2 of 19	NP_001295093.1
	GFM1	NM_001374355.1		c.127A>T	p.Asn43Tyr	missense	Exon 2 of 18	NP_001361284.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFM1	ENST00000486715.6	TSL:1 MANE Select	c.127A>T	p.Asn43Tyr	missense	Exon 2 of 18	ENSP00000419038.1
	GFM1	ENST00000264263.9	TSL:5	c.127A>T	p.Asn43Tyr	missense	Exon 2 of 19	ENSP00000264263.5
	GFM1	ENST00000478576.5	TSL:2	c.127A>T	p.Asn43Tyr	missense	Exon 2 of 14	ENSP00000418755.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.016	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.57	N
REVEL	Uncertain	0.43
Sift	Benign	0.86	T
Sift4G	Benign	1.0	T
Polyphen		0.97	D
Vest4		0.78
MutPred		0.41		Loss of disorder (P = 0.049)
MVP		0.79
MPC		0.31
ClinPred		0.76	D
GERP RS		5.4
Varity_R		0.36
gMVP		0.91
Mutation Taster		=244/56	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: rs35942089; hg19: chr3-158363463;