NM_021927.3:c.41C>G

Variant names:

• chr4-44678663-C-G
• rs778459305
• NM_021927.3:c.41C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021927.3(GUF1):​c.41C>G​(p.Ala14Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,337,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A14T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: GUF1 NM_021927.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.191
• Publications: 0 publications found

Genes affected

GUF1 (HGNC:25799): (GTP binding elongation factor GUF1) This gene encodes a GTPase that triggers back-translocation of the elongating ribosome during mitochondrial protein synthesis. The protein contains a highly conserved C-terminal domain not found in other GTPases that facilitates tRNA binding. The encoded protein is thought to prevent misincorporation of amino acids in stressful, suboptimal conditions. An allelic variant in this gene has been associated with early infantile epileptic encephalopathy-40. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

YIPF7 (HGNC:26825): (Yip1 domain family member 7) Predicted to be involved in endoplasmic reticulum to Golgi vesicle-mediated transport and vesicle fusion with Golgi apparatus. Predicted to be located in endoplasmic reticulum membrane. Predicted to be integral component of membrane. Predicted to be active in trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06909189).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021927.3. 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
	GUF1	NM_021927.3	MANE Select	c.41C>G	p.Ala14Gly	missense	Exon 1 of 17	NP_068746.2	Q8N442
	GUF1	NM_001345868.2		c.41C>G	p.Ala14Gly	missense	Exon 1 of 16	NP_001332797.1
	GUF1	NM_001345867.2		c.-928C>G		5_prime_UTR	Exon 1 of 17	NP_001332796.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUF1	ENST00000281543.6	TSL:1 MANE Select	c.41C>G	p.Ala14Gly	missense	Exon 1 of 17	ENSP00000281543.5	Q8N442
	GUF1	ENST00000513775.1	TSL:1	n.41C>G		non_coding_transcript_exon	Exon 1 of 9	ENSP00000422681.1	D6RBJ0
	GUF1	ENST00000953400.1		c.41C>G	p.Ala14Gly	missense	Exon 1 of 17	ENSP00000623459.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000864 AC: 1 AN: 115796 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1337458 Hom.: 0 Cov.: 31 AF XY: 0.00000151 AC XY: 1 AN XY: 660564

African (AFR) AF: 0.00 AC: 0 AN: 25898

American (AMR) AF: 0.0000564 AC: 1 AN: 17716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21592

East Asian (EAS) AF: 0.00 AC: 0 AN: 31310

South Asian (SAS) AF: 0.00 AC: 0 AN: 65682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4742

European-Non Finnish (NFE) AF: 9.38e-7 AC: 1 AN: 1066040

Other (OTH) AF: 0.00 AC: 0 AN: 54970

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000855 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	9.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.19
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.18
Sift	Uncertain	0.022	D
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.30		Gain of helix (P = 0.0082)
MVP		0.36
MPC		0.078
ClinPred		0.071	T
GERP RS		-0.043
PromoterAI		-0.43	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.49
Mutation Taster		=97/3	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: rs778459305; hg19: chr4-44680680;