17-81559406-G-T

Variant names:

• chr17-81559406-G-T
• rs201095089
• ENST00000573519.5:c.338C>A

Variant summary

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

The NM_001438810.1(NPLOC4):​c.1739C>A​(p.Ala580Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A580V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NPLOC4 NM_001438810.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.89
• 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=0.06814703).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438810.1. 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.1680C>A	p.Gly560Gly	synonymous	Exon 17 of 17	NP_060391.2	Q8TAT6-1
	NPLOC4	NM_001438810.1		c.1739C>A	p.Ala580Glu	missense	Exon 18 of 18	NP_001425739.1
	NPLOC4	NM_001369698.1		c.1695C>A	p.Gly565Gly	synonymous	Exon 17 of 17	NP_001356627.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPLOC4	ENST00000573519.5	TSL:1	c.338C>A	p.Ala113Glu	missense	Exon 5 of 5	ENSP00000459457.1	I3L281
	NPLOC4	ENST00000572760.5	TSL:1	c.74C>A	p.Ala25Glu	missense	Exon 3 of 3	ENSP00000467400.1	K7EJN1
	NPLOC4	ENST00000331134.11	TSL:1 MANE Select	c.1680C>A	p.Gly560Gly	synonymous	Exon 17 of 17	ENSP00000331487.5	Q8TAT6-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456948 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724376

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 43946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 85354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110020

Other (OTH) AF: 0.00 AC: 0 AN: 60148

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.086
DANN	Benign	0.84
DEOGEN2	Benign	0.010	T
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.068	T
PhyloP100		-3.9
Sift4G	Benign	0.45	T
Vest4		0.081
MVP		0.61
GERP RS		-9.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7

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: rs201095089; hg19: chr17-79526432;