1-156048508-C-T

Position:

• chr1-156048508-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_020131.5(UBQLN4):​c.893G>A​(p.Arg298Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00837 in 1,608,944 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0058 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (81 hom.)
• Consequence: UBQLN4 NM_020131.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.15

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 -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, UBQLN4
• BP4: Computational evidence support a benign effect (MetaRNN=0.008500159).
• BP6: Variant 1-156048508-C-T is Benign according to our data. Variant chr1-156048508-C-T is described in ClinVar as [Benign]. Clinvar id is 787857.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00864 (12580/1456718) while in subpopulation SAS AF= 0.0172 (1478/86068). AF 95% confidence interval is 0.0164. There are 81 homozygotes in gnomad4_exome. There are 6528 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 890 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBQLN4	NM_020131.5	c.893G>A	p.Arg298Gln	missense_variant	5/11	ENST00000368309.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBQLN4	ENST00000368309.4	c.893G>A	p.Arg298Gln	missense_variant	5/11	1	NM_020131.5	P1
UBQLN4	ENST00000472638.1	n.648G>A		non_coding_transcript_exon_variant	5/5	5

Frequencies

GnomAD3 genomes AF: 0.00584 AC: 889 AN: 152108 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00925

Gnomad OTH AF: 0.00815

GnomAD3 exomes AF: 0.00739 AC: 1848 AN: 250028 Hom.: 19 AF XY: 0.00865 AC XY: 1170 AN XY: 135188

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00403

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0180

Gnomad FIN exome AF: 0.00181

Gnomad NFE exome AF: 0.00911

Gnomad OTH exome AF: 0.00834

GnomAD4 exome AF: 0.00864 AC: 12580 AN: 1456718 Hom.: 81 Cov.: 31 AF XY: 0.00902 AC XY: 6528 AN XY: 723856

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.00372

Gnomad4 ASJ exome AF: 0.00288

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0172

Gnomad4 FIN exome AF: 0.00184

Gnomad4 NFE exome AF: 0.00929

Gnomad4 OTH exome AF: 0.00646

GnomAD4 genome AF: 0.00585 AC: 890 AN: 152226 Hom.: 7 Cov.: 32 AF XY: 0.00555 AC XY: 413 AN XY: 74428

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00490

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00925

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00844 Hom.: 10

Bravo AF: 0.00578

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.00722 AC: 877

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00888

EpiControl AF: 0.0102

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Benign	0.48
DEOGEN2	Benign	0.0064	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.092
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.14	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.84	N
REVEL	Uncertain	0.42
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.35	B
Vest4		0.40
MVP		0.77
MPC		0.81
ClinPred		0.011	T
GERP RS		4.3
Varity_R		0.18
gMVP		0.77

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: rs143327773; hg19: chr1-156018299; COSMIC: COSV64148525;