2-135780371-C-G

Variant names:

• chr2-135780371-C-G
• rs2304602
• NM_014607.4:c.1374C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_014607.4(UBXN4):​c.1374C>G​(p.Ser458Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00071 in 1,613,540 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (16 hom.)
• Consequence: UBXN4 NM_014607.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50
• Publications: 6 publications found

Genes affected

UBXN4 (HGNC:14860): (UBX domain protein 4) UBXD2 is an integral membrane protein of the endoplasmic reticulum (ER) that binds valosin-containing protein (VCP; MIM 601023) and promotes ER-associated protein degradation (ERAD) (Liang et al., 2006 [PubMed 16968747]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002482921).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00114 (173/152188) while in subpopulation EAS AF = 0.0272 (141/5182). AF 95% confidence interval is 0.0236. There are 2 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014607.4. 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
	UBXN4	NM_014607.4	MANE Select	c.1374C>G	p.Ser458Arg	missense	Exon 12 of 13	NP_055422.1	Q92575

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBXN4	ENST00000272638.14	TSL:1 MANE Select	c.1374C>G	p.Ser458Arg	missense	Exon 12 of 13	ENSP00000272638.9	Q92575
	UBXN4	ENST00000928826.1		c.1461C>G	p.Ser487Arg	missense	Exon 13 of 14	ENSP00000598885.1
	UBXN4	ENST00000928825.1		c.1404C>G	p.Ser468Arg	missense	Exon 12 of 13	ENSP00000598884.1

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152068 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0275

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00230 AC: 574 AN: 249288 AF XY: 0.00201

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0296

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000665 AC: 972 AN: 1461352 Hom.: 16 Cov.: 31 AF XY: 0.000666 AC XY: 484 AN XY: 727002

African (AFR) AF: 0.0000897 AC: 3 AN: 33448

American (AMR) AF: 0.0000224 AC: 1 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0180 AC: 715 AN: 39696

South Asian (SAS) AF: 0.00102 AC: 88 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111734

Other (OTH) AF: 0.00262 AC: 158 AN: 60376

GnomAD4 genome AF: 0.00114 AC: 173 AN: 152188 Hom.: 2 Cov.: 32 AF XY: 0.00120 AC XY: 89 AN XY: 74406

African (AFR) AF: 0.000289 AC: 12 AN: 41526

American (AMR) AF: 0.000196 AC: 3 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0272 AC: 141 AN: 5182

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000811 Hom.: 3

Bravo AF: 0.00121

ESP6500AA AF: 0.000270 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00226 AC: 273

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.029
Eigen_PC	Benign	0.052
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.5
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.14
Sift	Uncertain	0.015	D
Sift4G	Benign	0.44	T
Polyphen		0.44	B
Vest4		0.25
MutPred		0.12		Loss of phosphorylation at S458 (P = 0.0037)
MVP		0.068
MPC		0.37
ClinPred		0.021	T
GERP RS		4.2
Varity_R		0.16
gMVP		0.63
Mutation Taster		=81/19	polymorphism

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: rs2304602; hg19: chr2-136537941;