chr17-81569088-A-T

Variant names:

• chr17-81569088-A-T
• rs779900595
• NM_017921.4:c.1377T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017921.4(NPLOC4):​c.1377T>A​(p.Asp459Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NPLOC4 NM_017921.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.50
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15900922).

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.1377T>A	p.Asp459Glu	missense	Exon 14 of 17	NP_060391.2	Q8TAT6-1
	NPLOC4	NM_001437986.1		c.1377T>A	p.Asp459Glu	missense	Exon 14 of 16	NP_001424915.1
	NPLOC4	NM_001369698.1		c.1392T>A	p.Asp464Glu	missense	Exon 14 of 17	NP_001356627.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPLOC4	ENST00000331134.11	TSL:1 MANE Select	c.1377T>A	p.Asp459Glu	missense	Exon 14 of 17	ENSP00000331487.5	Q8TAT6-1
	NPLOC4	ENST00000705719.1		c.1506T>A	p.Asp502Glu	missense	Exon 14 of 17	ENSP00000516165.1	A0A994J7H4
	NPLOC4	ENST00000374747.9	TSL:2	c.1377T>A	p.Asp459Glu	missense	Exon 14 of 16	ENSP00000363879.5	Q8TAT6-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460170 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726508

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110504

Other (OTH) AF: 0.00 AC: 0 AN: 60314

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.52	N
PhyloP100		2.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.12
Sift	Benign	0.97	T
Sift4G	Benign	1.0	T
Polyphen		0.016	B
Vest4		0.13
MutPred		0.42		Gain of ubiquitination at K458 (P = 0.078)
MVP		0.53
MPC		0.90
ClinPred		0.51	D
GERP RS		2.1
PromoterAI		0.0039	Neutral
Varity_R		0.041
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs779900595; hg19: chr17-79536114;