rs2297792

Positions:

• chr1-156041653-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020131.5(UBQLN4):​c.1485A>G​(p.Ile495Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 1,565,318 control chromosomes in the GnomAD database, including 280,130 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.54 (23397 hom., cov: 33)
  • Exomes 𝑓: 0.60 (256733 hom.)
• Consequence: UBQLN4 NM_020131.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.716

Genes affected

UBQLN4 (HGNC:1237): (ubiquilin 4) Enables K48-linked polyubiquitin modification-dependent protein binding activity and identical protein binding activity. Involved in cellular response to DNA damage stimulus; negative regulation of double-strand break repair via homologous recombination; and regulation of cellular catabolic process. Located in several cellular components, including autophagosome; nucleoplasm; and site of DNA damage. Part of protein-containing complex. Colocalizes with cytosolic proteasome complex and nuclear proteasome complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.676082E-6).
• BP6: Variant 1-156041653-T-C is Benign according to our data. Variant chr1-156041653-T-C is described in ClinVar as [Benign]. Clinvar id is 674310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBQLN4	NM_020131.5	c.1485A>G	p.Ile495Met	missense_variant	10/11	ENST00000368309.4	NP_064516.2
UBQLN4	NM_001304342.2	c.1425A>G	p.Ile475Met	missense_variant	10/11		NP_001291271.1
UBQLN4	XM_024448469.2	c.1485A>G	p.Ile495Met	missense_variant	10/11		XP_024304237.1
UBQLN4	XM_047425666.1	c.951A>G	p.Ile317Met	missense_variant	10/11		XP_047281622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBQLN4	ENST00000368309.4	c.1485A>G	p.Ile495Met	missense_variant	10/11	1	NM_020131.5	ENSP00000357292	P1

Frequencies

GnomAD3 genomes AF: 0.542 AC: 82370 AN: 151898 Hom.: 23377 Cov.: 33

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.549

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.601

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.622

Gnomad OTH AF: 0.551

GnomAD3 exomes AF: 0.529 AC: 100560 AN: 189974 Hom.: 28165 AF XY: 0.537 AC XY: 55073 AN XY: 102564

Gnomad AFR exome AF: 0.432

Gnomad AMR exome AF: 0.451

Gnomad ASJ exome AF: 0.578

Gnomad EAS exome AF: 0.127

Gnomad SAS exome AF: 0.523

Gnomad FIN exome AF: 0.594

Gnomad NFE exome AF: 0.618

Gnomad OTH exome AF: 0.559

GnomAD4 exome AF: 0.596 AC: 841922 AN: 1413302 Hom.: 256733 Cov.: 58 AF XY: 0.595 AC XY: 415849 AN XY: 699304

Gnomad4 AFR exome AF: 0.429

Gnomad4 AMR exome AF: 0.462

Gnomad4 ASJ exome AF: 0.588

Gnomad4 EAS exome AF: 0.151

Gnomad4 SAS exome AF: 0.529

Gnomad4 FIN exome AF: 0.607

Gnomad4 NFE exome AF: 0.626

Gnomad4 OTH exome AF: 0.577

GnomAD4 genome AF: 0.542 AC: 82419 AN: 152016 Hom.: 23397 Cov.: 33 AF XY: 0.539 AC XY: 40032 AN XY: 74314

Gnomad4 AFR AF: 0.439

Gnomad4 AMR AF: 0.548

Gnomad4 ASJ AF: 0.586

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.537

Gnomad4 FIN AF: 0.601

Gnomad4 NFE AF: 0.622

Gnomad4 OTH AF: 0.552

Alfa AF: 0.593 Hom.: 53601

Bravo AF: 0.530

TwinsUK AF: 0.626 AC: 2323

ALSPAC AF: 0.629 AC: 2424

ESP6500AA AF: 0.436 AC: 1918

ESP6500EA AF: 0.613 AC: 5274

ExAC AF: 0.512 AC: 61077

Asia WGS AF: 0.373 AC: 1295 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Benign	0.74
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.052	T
MetaRNN	Benign	0.0000057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.029
Sift	Benign	0.42	T
Sift4G	Benign	0.27	T
Polyphen		0.0070	B
Vest4		0.021
MPC		0.67
ClinPred		0.0014	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.051
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs2297792; hg19: chr1-156011444; COSMIC: COSV64149079; COSMIC: COSV64149079;