17-81559353-G-A

Variant names:

• chr17-81559353-G-A
• rs113318717
• NM_017921.4:c.1733C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_017921.4(NPLOC4):​c.1733C>T​(p.Thr578Met) variant causes a missense change. The variant allele was found at a frequency of 0.00119 in 1,607,754 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T578A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0054 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (5 hom.)
• Consequence: NPLOC4 NM_017921.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.95
• Publications: 4 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003497541).
• BP6: Variant 17-81559353-G-A is Benign according to our data. Variant chr17-81559353-G-A is described in ClinVar as [Benign]. Clinvar id is 777257.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00536 (816/152354) while in subpopulation AFR AF = 0.0184 (767/41588). AF 95% confidence interval is 0.0174. There are 9 homozygotes in GnomAd4. There are 382 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPLOC4	NM_017921.4	c.1733C>T	p.Thr578Met	missense_variant	Exon 17 of 17	ENST00000331134.11	NP_060391.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPLOC4	ENST00000331134.11	c.1733C>T	p.Thr578Met	missense_variant	Exon 17 of 17	1	NM_017921.4	ENSP00000331487.5

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 810 AN: 152236 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00163

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00154 AC: 360 AN: 233520 AF XY: 0.00118

Gnomad AFR exome AF: 0.0207

Gnomad AMR exome AF: 0.000848

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.000230

Gnomad FIN exome AF: 0.0000515

Gnomad NFE exome AF: 0.000285

Gnomad OTH exome AF: 0.000702

GnomAD4 exome AF: 0.000758 AC: 1103 AN: 1455400 Hom.: 5 Cov.: 30 AF XY: 0.000697 AC XY: 504 AN XY: 723434

African (AFR) AF: 0.0220 AC: 734 AN: 33402

American (AMR) AF: 0.00101 AC: 44 AN: 43718

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25986

East Asian (EAS) AF: 0.0000760 AC: 3 AN: 39488

South Asian (SAS) AF: 0.000118 AC: 10 AN: 85098

European-Finnish (FIN) AF: 0.0000572 AC: 3 AN: 52456

Middle Eastern (MID) AF: 0.00263 AC: 15 AN: 5704

European-Non Finnish (NFE) AF: 0.000167 AC: 185 AN: 1109462

Other (OTH) AF: 0.00180 AC: 108 AN: 60086

GnomAD4 genome AF: 0.00536 AC: 816 AN: 152354 Hom.: 9 Cov.: 33 AF XY: 0.00513 AC XY: 382 AN XY: 74508

African (AFR) AF: 0.0184 AC: 767 AN: 41588

American (AMR) AF: 0.00163 AC: 25 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68032

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00162 Hom.: 2

Bravo AF: 0.00657

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0201 AC: 84

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00192 AC: 232

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.84
DEOGEN2	Benign	0.0070	.;.;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.63	.;T;T
MetaRNN	Benign	0.0035	T;T;T
PhyloP100		4.0
Sift4G	Uncertain	0.028	.;.;D
Vest4		0.18
MVP		0.35
ClinPred		0.010	T
GERP RS		1.6
Varity_R		0.021
Mutation Taster		=98/2	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: rs113318717; hg19: chr17-79526379;