rs578188683

Variant names:

• chr17-81569036-C-G
• rs578188683
• NM_017921.4:c.1429G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-81569036-C-G
• chr17-81569036-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_017921.4(NPLOC4):​c.1429G>C​(p.Asp477His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,610,094 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts 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. D477N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (4 hom.)
• Consequence: NPLOC4 NM_017921.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.41
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12580538).
• BS2: High Homozygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPLOC4	NM_017921.4	c.1429G>C	p.Asp477His	missense_variant	Exon 14 of 17	ENST00000331134.11	NP_060391.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPLOC4	ENST00000331134.11	c.1429G>C	p.Asp477His	missense_variant	Exon 14 of 17	1	NM_017921.4	ENSP00000331487.5

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000425 AC: 106 AN: 249194 AF XY: 0.000362

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00364

GnomAD4 exome AF: 0.000236 AC: 344 AN: 1457820 Hom.: 4 Cov.: 29 AF XY: 0.000221 AC XY: 160 AN XY: 725540

African (AFR) AF: 0.0000898 AC: 3 AN: 33396

American (AMR) AF: 0.00181 AC: 81 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000302 AC: 26 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5760

European-Non Finnish (NFE) AF: 0.000146 AC: 162 AN: 1108330

Other (OTH) AF: 0.000913 AC: 55 AN: 60268

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74450

African (AFR) AF: 0.0000481 AC: 2 AN: 41566

American (AMR) AF: 0.00216 AC: 33 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000670 Hom.: 0

Bravo AF: 0.000657

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000463 AC: 56

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.1	M;.;M
PhyloP100		7.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.6	N;.;.
REVEL	Uncertain	0.48
Sift	Benign	0.51	T;.;.
Sift4G	Benign	0.54	T;T;T
Polyphen		0.92	P;.;P
Vest4		0.54
MVP		0.79
MPC		2.1
ClinPred		0.85	D
GERP RS		5.6
PromoterAI		-0.00060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.75
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs578188683; hg19: chr17-79536062;