rs879255631

chr4-44695724-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_021927.3(GUF1):c.1825G>T(p.Ala609Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GUF1 NM_021927.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.59

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]

GNPDA2 (HGNC:21526): (glucosamine-6-phosphate deaminase 2) The protein encoded by this gene is an allosteric enzyme that catalyzes the reversible reaction converting D-glucosamine-6-phosphate into D-fructose-6-phosphate and ammonium. Variations of this gene have been reported to be associated with influencing body mass index and susceptibility to obesity. A pseudogene of this gene is located on chromosome 9. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 4-44695724-G-T is Pathogenic according to our data. Variant chr4-44695724-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 253096.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-44695724-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUF1	NM_021927.3	c.1825G>T	p.Ala609Ser	missense_variant	15/17	ENST00000281543.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUF1	ENST00000281543.6	c.1825G>T	p.Ala609Ser	missense_variant	15/17	1	NM_021927.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000808 AC: 2 AN: 247640 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133716

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458448 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725380

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 40 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.70
Sift	Benign	0.044	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.84		Gain of catalytic residue at A609 (P = 0.039);
MVP		0.85
MPC		0.37
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.77

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

LitVar

Other links and lift over

dbSNP: rs879255631; hg19: chr4-44697741;