17-81559362-G-C

Variant names:

• chr17-81559362-G-C
• NM_017921.4:c.1724C>G

Variant summary

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

The NM_017921.4(NPLOC4):​c.1724C>G​(p.Ser575Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S575T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NPLOC4 NM_017921.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.13
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1724C>G	p.Ser575Cys	missense	Exon 17 of 17	NP_060391.2	Q8TAT6-1
	NPLOC4	NM_001369698.1		c.1739C>G	p.Ser580Cys	missense	Exon 17 of 17	NP_001356627.1
	NPLOC4	NM_001438810.1		c.1783C>G	p.Pro595Ala	missense	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.1724C>G	p.Ser575Cys	missense	Exon 17 of 17	ENSP00000331487.5	Q8TAT6-1
	NPLOC4	ENST00000573519.5	TSL:1	c.382C>G	p.Pro128Ala	missense	Exon 5 of 5	ENSP00000459457.1	I3L281
	NPLOC4	ENST00000572760.5	TSL:1	c.118C>G	p.Pro40Ala	missense	Exon 3 of 3	ENSP00000467400.1	K7EJN1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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	0.10
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.75
DEOGEN2	Benign	0.0097	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.73	D
PhyloP100		9.1
Sift4G	Benign	0.14	T
Vest4		0.18
MVP		0.87
ClinPred		0.76	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18

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

hg19: chr17-79526388;