17-81559375-C-T

Variant names:

• chr17-81559375-C-T
• rs760752376
• NM_017921.4:c.1711G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017921.4(NPLOC4):​c.1711G>A​(p.Ala571Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,609,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: NPLOC4 NM_017921.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.74
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3561716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPLOC4	NM_017921.4	c.1711G>A	p.Ala571Thr	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.1711G>A	p.Ala571Thr	missense_variant	Exon 17 of 17	1	NM_017921.4	ENSP00000331487.5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000168 AC: 4 AN: 237592 AF XY: 0.0000154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000280

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1457598 Hom.: 0 Cov.: 30 AF XY: 0.0000221 AC XY: 16 AN XY: 724718

African (AFR) AF: 0.0000299 AC: 1 AN: 33432

American (AMR) AF: 0.0000680 AC: 3 AN: 44108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39562

South Asian (SAS) AF: 0.0000351 AC: 3 AN: 85454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1110388

Other (OTH) AF: 0.0000166 AC: 1 AN: 60164

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74378

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

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

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1711G>A (p.A571T) alteration is located in exon 17 (coding exon 17) of the NPLOC4 gene. This alteration results from a G to A substitution at nucleotide position 1711, causing the alanine (A) at amino acid position 571 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.0099	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.3	L
PhyloP100		6.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.23
Sift	Benign	0.068	T
Sift4G	Uncertain	0.048	D
Polyphen		0.0050	B
Vest4		0.63
MutPred		0.29		Gain of relative solvent accessibility (P = 0.0023);
MVP		0.63
MPC		0.013
ClinPred		0.32	T
GERP RS		5.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.13
gMVP		0.32
Mutation Taster		=64/36	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: rs760752376; hg19: chr17-79526401;