rs116062572

Variant names:

• chr4-44686523-C-T
• rs116062572
• NM_021927.3:c.748C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001345867.2(GUF1):​c.-225C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00388 in 1,610,132 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (16 hom.)
• Consequence: GUF1 NM_001345867.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.805
• Publications: 3 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]

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038073063).
• BP6: Variant 4-44686523-C-T is Benign according to our data. Variant chr4-44686523-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445372.
• BS2: High AC in GnomAd4 at 466 AD,Unknown gene.

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.748C>T	p.Arg250Cys	missense	Exon 8 of 17	NP_068746.2
	GUF1	NM_001345867.2		c.-225C>T		5_prime_UTR_premature_start_codon_gain	Exon 8 of 17	NP_001332796.1
	GUF1	NM_001345869.2		c.-225C>T		5_prime_UTR_premature_start_codon_gain	Exon 7 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.748C>T	p.Arg250Cys	missense	Exon 8 of 17	ENSP00000281543.5
	GUF1	ENST00000513775.1	TSL:1	n.*339C>T		non_coding_transcript_exon	Exon 7 of 9	ENSP00000422681.1
	GUF1	ENST00000513775.1	TSL:1	n.*339C>T		3_prime_UTR	Exon 7 of 9	ENSP00000422681.1

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 466 AN: 151868 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000991

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00441

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00505

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00234 AC: 585 AN: 250528 AF XY: 0.00231

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000742

Gnomad NFE exome AF: 0.00403

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00397 AC: 5784 AN: 1458146 Hom.: 16 Cov.: 30 AF XY: 0.00383 AC XY: 2776 AN XY: 725506

African (AFR) AF: 0.000540 AC: 18 AN: 33358

American (AMR) AF: 0.00249 AC: 111 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26014

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39584

South Asian (SAS) AF: 0.000314 AC: 27 AN: 85994

European-Finnish (FIN) AF: 0.000844 AC: 45 AN: 53326

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5752

European-Non Finnish (NFE) AF: 0.00484 AC: 5369 AN: 1109296

Other (OTH) AF: 0.00347 AC: 209 AN: 60220

GnomAD4 genome AF: 0.00307 AC: 466 AN: 151986 Hom.: 1 Cov.: 32 AF XY: 0.00299 AC XY: 222 AN XY: 74312

African (AFR) AF: 0.000988 AC: 41 AN: 41498

American (AMR) AF: 0.00440 AC: 67 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000755 AC: 8 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00505 AC: 343 AN: 67898

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

Alfa AF: 0.00318 Hom.: 1

Bravo AF: 0.00309

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00454 AC: 39

ExAC AF: 0.00227 AC: 276

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	GUF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.81
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.035
Sift	Benign	0.077	T
Sift4G	Benign	0.11	T
Polyphen		0.0010	B
Vest4		0.11
MVP		0.27
MPC		0.078
ClinPred		0.015	T
GERP RS		3.3
Varity_R		0.087
gMVP		0.40
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs116062572; hg19: chr4-44688540; COSMIC: COSV99029373;