chr5-74767056-C-T

Variant names:

• chr5-74767056-C-T
• rs11556477
• NM_032380.5:c.-143G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BA1

The NM_032380.5(GFM2):​c.-143G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0781 in 370,706 control chromosomes in the GnomAD database, including 1,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (614 hom., cov: 33)
  • Exomes 𝑓: 0.081 (919 hom.)
• Consequence: GFM2 NM_032380.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0500
• Publications: 7 publications found

Genes affected

GFM2 (HGNC:29682): (GTP dependent ribosome recycling factor mitochondrial 2) 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, which is a GTPase that plays a role at the termination of mitochondrial translation by mediating the disassembly of ribosomes from messenger RNA . Its role in the regulation of normal mitochondrial function and in disease states attributed to mitochondrial dysfunction is not known. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2013]

NSA2 (HGNC:30728): (NSA2 ribosome biogenesis factor) This gene encodes a nucleolar protein involved in cell cycle regulation and proliferation. This gene was identified based on sequence similarity to a highly conserved Saccharomyces cerevisiae gene encoding a pre-ribosomal protein, which is involved in large ribosomal subunit biogenesis. The encoded protein is found at elevated levels in diabetic nephropathy. Alternative splicing results in multiple transcript variants. Several related pseudogenes have been identified. [provided by RefSeq, Nov 2012]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 5-74767056-C-T is Benign according to our data. Variant chr5-74767056-C-T is described in ClinVar as Benign. ClinVar VariationId is 1267778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032380.5. 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
	GFM2	NM_032380.5	MANE Select	c.-143G>A		5_prime_UTR	Exon 1 of 21	NP_115756.2
	GFM2	NM_001281302.2		c.-165G>A		5_prime_UTR	Exon 1 of 22	NP_001268231.1
	GFM2	NM_170691.3		c.-143G>A		5_prime_UTR	Exon 1 of 20	NP_733792.1	Q969S9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFM2	ENST00000296805.8	TSL:1 MANE Select	c.-143G>A		5_prime_UTR	Exon 1 of 21	ENSP00000296805.3	Q969S9-1
	GFM2	ENST00000509430.5	TSL:1	c.-261G>A		5_prime_UTR	Exon 1 of 22	ENSP00000427004.1	Q969S9-1
	GFM2	ENST00000345239.6	TSL:1	c.-143G>A		5_prime_UTR	Exon 1 of 20	ENSP00000296804.3	Q969S9-2

Frequencies

GnomAD3 genomes AF: 0.0740 AC: 11261 AN: 152252 Hom.: 614 Cov.: 33

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.0839

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0424

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0793

Gnomad OTH AF: 0.0951

GnomAD4 exome AF: 0.0811 AC: 17697 AN: 218336 Hom.: 919 Cov.: 0 AF XY: 0.0821 AC XY: 9368 AN XY: 114046

African (AFR) AF: 0.0243 AC: 165 AN: 6790

American (AMR) AF: 0.169 AC: 1574 AN: 9332

Ashkenazi Jewish (ASJ) AF: 0.0806 AC: 583 AN: 7234

East Asian (EAS) AF: 0.129 AC: 2050 AN: 15948

South Asian (SAS) AF: 0.107 AC: 2140 AN: 19908

European-Finnish (FIN) AF: 0.0390 AC: 566 AN: 14524

Middle Eastern (MID) AF: 0.0975 AC: 92 AN: 944

European-Non Finnish (NFE) AF: 0.0721 AC: 9410 AN: 130524

Other (OTH) AF: 0.0851 AC: 1117 AN: 13132

GnomAD4 genome AF: 0.0739 AC: 11265 AN: 152370 Hom.: 614 Cov.: 33 AF XY: 0.0751 AC XY: 5596 AN XY: 74514

African (AFR) AF: 0.0232 AC: 964 AN: 41594

American (AMR) AF: 0.160 AC: 2456 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0839 AC: 291 AN: 3470

East Asian (EAS) AF: 0.164 AC: 851 AN: 5178

South Asian (SAS) AF: 0.121 AC: 584 AN: 4832

European-Finnish (FIN) AF: 0.0424 AC: 451 AN: 10628

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0792 AC: 5392 AN: 68038

Other (OTH) AF: 0.0946 AC: 200 AN: 2114

Alfa AF: 0.0741 Hom.: 236

Bravo AF: 0.0813

Asia WGS AF: 0.149 AC: 519 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	7.0
DANN	Benign	0.68
PhyloP100		-0.050
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.94		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11556477; hg19: chr5-74062881;