chr17-81559378-C-T

Variant names:

• chr17-81559378-C-T
• rs765749847
• NM_017921.4:c.1708G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017921.4(NPLOC4):​c.1708G>A​(p.Gly570Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,457,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: NPLOC4 NM_017921.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.20
• Publications: 0 publications found

Genes affected

NPLOC4 (HGNC:18261): (NPL4 homolog, ubiquitin recognition factor) Predicted to enable ATPase binding activity; ubiquitin binding activity; and ubiquitin protein ligase binding activity. Predicted to contribute to K48-linked polyubiquitin modification-dependent protein binding activity and K63-linked polyubiquitin modification-dependent protein binding activity. Involved in negative regulation of RIG-I signaling pathway; negative regulation of type I interferon production; and proteolysis involved in cellular protein catabolic process. Located in nucleus. Part of UFD1-NPL4 complex and VCP-NPL4-UFD1 AAA ATPase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20733616).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017921.4. 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
	NPLOC4	NM_017921.4	MANE Select	c.1708G>A	p.Gly570Ser	missense	Exon 17 of 17	NP_060391.2	Q8TAT6-1
	NPLOC4	NM_001369698.1		c.1723G>A	p.Gly575Ser	missense	Exon 17 of 17	NP_001356627.1
	NPLOC4	NM_001438810.1		c.1767G>A	p.Thr589Thr	synonymous	Exon 18 of 18	NP_001425739.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPLOC4	ENST00000331134.11	TSL:1 MANE Select	c.1708G>A	p.Gly570Ser	missense	Exon 17 of 17	ENSP00000331487.5	Q8TAT6-1
	NPLOC4	ENST00000573519.5	TSL:1	c.366G>A	p.Thr122Thr	synonymous	Exon 5 of 5	ENSP00000459457.1	I3L281
	NPLOC4	ENST00000572760.5	TSL:1	c.102G>A	p.Thr34Thr	synonymous	Exon 3 of 3	ENSP00000467400.1	K7EJN1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000210 AC: 5 AN: 237988 AF XY: 0.0000385

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: 0.0000467

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1457730 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 724816

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39570

South Asian (SAS) AF: 0.00 AC: 0 AN: 85474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1110456

Other (OTH) AF: 0.0000332 AC: 2 AN: 60164

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.0077
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.19
Sift	Benign	0.39	T
Sift4G	Benign	0.46	T
Polyphen		0.022	B
Vest4		0.45
MutPred		0.29		Gain of glycosylation at G570 (P = 0.0054)
MVP		0.54
MPC		0.014
ClinPred		0.24	T
GERP RS		5.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.17
gMVP		0.30
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs765749847; hg19: chr17-79526404;