4-44678623-A-T

Variant names:

• chr4-44678623-A-T
• rs766517594
• NM_021927.3:c.1A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001345867.2(GUF1):​c.-968A>T variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GUF1 NM_001345867.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.69
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001345867.2. 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.1A>T	p.Met1?	initiator_codon	Exon 1 of 17	NP_068746.2	Q8N442
	GUF1	NM_001345867.2		c.-968A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001332796.1
	GUF1	NM_001345869.2		c.-860A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001332798.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUF1	ENST00000281543.6	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 17	ENSP00000281543.5	Q8N442
	GUF1	ENST00000513775.1	TSL:1	n.1A>T		non_coding_transcript_exon	Exon 1 of 9	ENSP00000422681.1	D6RBJ0
	GUF1	ENST00000953400.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 17	ENSP00000623459.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000863 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	20
DANN	Benign	0.87
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.64	T
PhyloP100		3.7
PROVEAN	Benign	-0.19	N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.17	B
Vest4		0.91
MutPred		0.92		Loss of solvent accessibility (P = 0.0595)
MVP		0.45
ClinPred		0.99	D
GERP RS		4.0
PromoterAI		-0.16	Neutral
Varity_R		0.96
gMVP		0.53
Mutation Taster		=38/162	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs766517594; hg19: chr4-44680640;