1-156044111-G-A

Position:

• chr1-156044111-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_020131.5(UBQLN4):​c.1013C>T​(p.Pro338Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,434,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UBQLN4 NM_020131.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.25

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, UBQLN4
• BP4: Computational evidence support a benign effect (MetaRNN=0.27165383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBQLN4	NM_020131.5	c.1013C>T	p.Pro338Leu	missense_variant	6/11	ENST00000368309.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBQLN4	ENST00000368309.4	c.1013C>T	p.Pro338Leu	missense_variant	6/11	1	NM_020131.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1434596 Hom.: 0 Cov.: 32 AF XY: 0.00000281 AC XY: 2 AN XY: 711460

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: 9.10e-7

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.086
Sift	Benign	0.066	T
Sift4G	Benign	0.17	T
Polyphen		0.65	P
Vest4		0.45
MutPred		0.18		Loss of glycosylation at P338 (P = 0.0074);
MVP		0.21
MPC		0.85
ClinPred		0.85	D
GERP RS		5.2
Varity_R		0.13
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1683638561; hg19: chr1-156013902;