3-132660628-G-T

Position:

• chr3-132660628-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001320210.2(UBA5):​c.-428G>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 0.000000708 in 1,413,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: UBA5 NM_001320210.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0560

Genes affected

UBA5 (HGNC:23230): (ubiquitin like modifier activating enzyme 5) This gene encodes a member of the E1-like ubiquitin-activating enzyme family. This protein activates ubiquitin-fold modifier 1, a ubiquitin-like post-translational modifier protein, via the formation of a high-energy thioester bond. Alternative splicing results in multiple transcript variants. A pseudogene of this gene has been identified on chromosome 1. [provided by RefSeq, Feb 2016]

NPHP3-ACAD11 (HGNC:48351): (NPHP3-ACAD11 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring NPHP3 (nephronophthisis 3, adolescent) and ACAD11 (acyl-CoA dehydrogenase family, member 11) genes on chromosome 3. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2645628).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBA5	NM_024818.6	c.91G>T	p.Gly31Cys	missense_variant	1/12	ENST00000356232.10	NP_079094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBA5	ENST00000356232.10	c.91G>T	p.Gly31Cys	missense_variant	1/12	1	NM_024818.6	ENSP00000348565.4
NPHP3-ACAD11	ENST00000632629.1	c.636-15732C>A		intron_variant		2		ENSP00000488520.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1413422 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 698540

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: 0.00

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.91G>T (p.G31C) alteration is located in exon 1 (coding exon 1) of the UBA5 gene. This alteration results from a G to T substitution at nucleotide position 91, causing the glycine (G) at amino acid position 31 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.0032	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;.
Eigen	Benign	-0.059
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.56	T;T;T
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Uncertain	-0.0075	T
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.63	N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.017	D;D;D
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.96	D;.;D
Vest4		0.089
MutPred		0.31		Loss of MoRF binding (P = 0.0778);Loss of MoRF binding (P = 0.0778);Loss of MoRF binding (P = 0.0778);
MVP		0.29
MPC		0.64
ClinPred		0.80	D
GERP RS		4.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.7
Varity_R		0.20
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-132379472;