5-74767056-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -14 ACMG points.

• PP3: Splicing scoreres supports a deletorius 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFM2	NM_032380.5	c.-143G>A		5_prime_UTR_variant	Exon 1 of 21	ENST00000296805.8	NP_115756.2
NSA2	NM_014886.6	c.-305C>T		upstream_gene_variant		ENST00000610426.5	NP_055701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFM2	ENST00000296805.8	c.-143G>A		5_prime_UTR_variant	Exon 1 of 21	1	NM_032380.5	ENSP00000296805.3
NSA2	ENST00000610426.5	c.-305C>T		upstream_gene_variant		1	NM_014886.6	ENSP00000483484.1

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

Gnomad4 AFR exome AF: 0.0243

Gnomad4 AMR exome AF: 0.169

Gnomad4 ASJ exome AF: 0.0806

Gnomad4 EAS exome AF: 0.129

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.0390

Gnomad4 NFE exome AF: 0.0721

Gnomad4 OTH exome AF: 0.0851

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

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.160

Gnomad4 ASJ AF: 0.0839

Gnomad4 EAS AF: 0.164

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.0424

Gnomad4 NFE AF: 0.0792

Gnomad4 OTH AF: 0.0946

Alfa AF: 0.0722 Hom.: 190

Bravo AF: 0.0813

Asia WGS AF: 0.149 AC: 519 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	7.0
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs11556477; hg19: chr5-74062881;