17-81572047-C-A

Variant names:

• chr17-81572047-C-A
• rs17852307
• NM_017921.4:c.1323G>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_017921.4(NPLOC4):​c.1323G>T​(p.Arg441Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00672 in 1,606,606 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (8 hom., cov: 30)
  • Exomes 𝑓: 0.0069 (45 hom.)
• Consequence: NPLOC4 NM_017921.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.36
• Publications: 5 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 17-81572047-C-A is Benign according to our data. Variant chr17-81572047-C-A is described in ClinVar as [Benign]. Clinvar id is 789902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.36 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPLOC4	NM_017921.4	c.1323G>T	p.Arg441Arg	synonymous_variant	Exon 13 of 17	ENST00000331134.11	NP_060391.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPLOC4	ENST00000331134.11	c.1323G>T	p.Arg441Arg	synonymous_variant	Exon 13 of 17	1	NM_017921.4	ENSP00000331487.5

Frequencies

GnomAD3 genomes AF: 0.00500 AC: 753 AN: 150620 Hom.: 8 Cov.: 30

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00594

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00128

Gnomad FIN AF: 0.000864

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00831

Gnomad OTH AF: 0.00437

GnomAD2 exomes AF: 0.00396 AC: 979 AN: 246914 AF XY: 0.00396

Gnomad AFR exome AF: 0.000856

Gnomad AMR exome AF: 0.00175

Gnomad ASJ exome AF: 0.00190

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000700

Gnomad NFE exome AF: 0.00681

Gnomad OTH exome AF: 0.00535

GnomAD4 exome AF: 0.00690 AC: 10041 AN: 1455868 Hom.: 45 Cov.: 30 AF XY: 0.00668 AC XY: 4835 AN XY: 724338

African (AFR) AF: 0.00117 AC: 39 AN: 33414

American (AMR) AF: 0.00229 AC: 102 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00216 AC: 56 AN: 25978

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00248 AC: 212 AN: 85394

European-Finnish (FIN) AF: 0.00117 AC: 62 AN: 53152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00830 AC: 9194 AN: 1107908

Other (OTH) AF: 0.00626 AC: 376 AN: 60030

GnomAD4 genome AF: 0.00500 AC: 753 AN: 150738 Hom.: 8 Cov.: 30 AF XY: 0.00426 AC XY: 313 AN XY: 73528

African (AFR) AF: 0.00178 AC: 73 AN: 40960

American (AMR) AF: 0.00593 AC: 89 AN: 15002

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 4 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00128 AC: 6 AN: 4696

European-Finnish (FIN) AF: 0.000864 AC: 9 AN: 10420

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

European-Non Finnish (NFE) AF: 0.00831 AC: 563 AN: 67748

Other (OTH) AF: 0.00432 AC: 9 AN: 2082

Alfa AF: 0.00626 Hom.: 2

Bravo AF: 0.00535

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.6
DANN	Benign	0.84
PhyloP100		-1.4
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs17852307; hg19: chr17-79539073; COSMIC: COSV100480772; COSMIC: COSV100480772;