3-132675903-G-T

Variant names:

• chr3-132675903-G-T
• rs114925667
• NM_024818.6:c.1111G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_024818.6(UBA5):​c.1111G>T​(p.Ala371Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,214 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A371T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: UBA5 NM_024818.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.94
• Publications: 24 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-132675903-G-A is described in ClinVar as Pathogenic/Likely_pathogenic/Pathogenic,_low_penetrance. ClinVar VariationId is 265745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024818.6. 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
	UBA5	NM_024818.6	MANE Select	c.1111G>T	p.Ala371Ser	missense	Exon 11 of 12	NP_079094.1	Q9GZZ9-1
	UBA5	NM_001320210.2		c.943G>T	p.Ala315Ser	missense	Exon 11 of 12	NP_001307139.1	Q9GZZ9-2
	UBA5	NM_198329.4		c.943G>T	p.Ala315Ser	missense	Exon 11 of 12	NP_938143.1	Q9GZZ9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBA5	ENST00000356232.10	TSL:1 MANE Select	c.1111G>T	p.Ala371Ser	missense	Exon 11 of 12	ENSP00000348565.4	Q9GZZ9-1
	UBA5	ENST00000494238.6	TSL:1	c.943G>T	p.Ala315Ser	missense	Exon 11 of 12	ENSP00000418807.2	Q9GZZ9-2
	NPHP3-ACAD11	ENST00000632629.1	TSL:2	c.635+6011C>A		intron	N/A	ENSP00000488520.1	A0A0J9YXS1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243374 AF XY: 0.00000759

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449214 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720346

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32902

American (AMR) AF: 0.00 AC: 0 AN: 42040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25624

East Asian (EAS) AF: 0.00 AC: 0 AN: 39462

South Asian (SAS) AF: 0.00 AC: 0 AN: 83214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5348

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107562

Other (OTH) AF: 0.00 AC: 0 AN: 59902

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.57
Sift	Benign	0.12	T
Sift4G	Benign	0.12	T
Polyphen		0.94	P
Vest4		0.62
MutPred		0.46		Gain of disorder (P = 0.0103)
MVP		0.58
MPC		0.39
ClinPred		0.70	D
GERP RS		5.4
Varity_R		0.29
gMVP		0.51
Mutation Taster		=38/62	disease causing

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

Other links and lift over

dbSNP: rs114925667; hg19: chr3-132394747;