chr17-81629785-C-T

Variant names:

• chr17-81629785-C-T
• rs9894429
• NM_017921.4:c.36G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_017921.4(NPLOC4):​c.36G>A​(p.Pro12Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,611,098 control chromosomes in the GnomAD database, including 207,066 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.

• Frequency:
  • Genomes: 𝑓 0.57 (26334 hom., cov: 32)
  • Exomes 𝑓: 0.49 (180732 hom.)
• Consequence: NPLOC4 NM_017921.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.29
• Publications: 62 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP7: Synonymous conserved (PhyloP=-3.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

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.36G>A	p.Pro12Pro	synonymous	Exon 2 of 17	NP_060391.2	Q8TAT6-1
	NPLOC4	NM_001437986.1		c.36G>A	p.Pro12Pro	synonymous	Exon 2 of 16	NP_001424915.1
	NPLOC4	NM_001369698.1		c.36G>A	p.Pro12Pro	synonymous	Exon 2 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.36G>A	p.Pro12Pro	synonymous	Exon 2 of 17	ENSP00000331487.5	Q8TAT6-1
	NPLOC4	ENST00000705719.1		c.165G>A	p.Pro55Pro	synonymous	Exon 2 of 17	ENSP00000516165.1	A0A994J7H4
	NPLOC4	ENST00000374747.9	TSL:2	c.36G>A	p.Pro12Pro	synonymous	Exon 2 of 16	ENSP00000363879.5	Q8TAT6-2

Frequencies

GnomAD3 genomes AF: 0.568 AC: 86350 AN: 151916 Hom.: 26276 Cov.: 32

Gnomad AFR AF: 0.755

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.772

Gnomad SAS AF: 0.645

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.556

GnomAD2 exomes AF: 0.557 AC: 138841 AN: 249138 AF XY: 0.547

Gnomad AFR exome AF: 0.765

Gnomad AMR exome AF: 0.734

Gnomad ASJ exome AF: 0.511

Gnomad EAS exome AF: 0.774

Gnomad FIN exome AF: 0.428

Gnomad NFE exome AF: 0.452

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.488 AC: 712096 AN: 1459064 Hom.: 180732 Cov.: 34 AF XY: 0.490 AC XY: 355711 AN XY: 725958

African (AFR) AF: 0.766 AC: 25600 AN: 33438

American (AMR) AF: 0.723 AC: 32335 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 13386 AN: 26102

East Asian (EAS) AF: 0.744 AC: 29498 AN: 39674

South Asian (SAS) AF: 0.619 AC: 53370 AN: 86162

European-Finnish (FIN) AF: 0.436 AC: 23247 AN: 53376

Middle Eastern (MID) AF: 0.534 AC: 3072 AN: 5756

European-Non Finnish (NFE) AF: 0.451 AC: 499918 AN: 1109572

Other (OTH) AF: 0.525 AC: 31670 AN: 60284

GnomAD4 genome AF: 0.569 AC: 86463 AN: 152034 Hom.: 26334 Cov.: 32 AF XY: 0.569 AC XY: 42305 AN XY: 74286

African (AFR) AF: 0.755 AC: 31331 AN: 41482

American (AMR) AF: 0.624 AC: 9522 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 1796 AN: 3470

East Asian (EAS) AF: 0.772 AC: 3999 AN: 5178

South Asian (SAS) AF: 0.644 AC: 3099 AN: 4812

European-Finnish (FIN) AF: 0.427 AC: 4507 AN: 10554

Middle Eastern (MID) AF: 0.568 AC: 166 AN: 292

European-Non Finnish (NFE) AF: 0.448 AC: 30468 AN: 67974

Other (OTH) AF: 0.562 AC: 1187 AN: 2112

Alfa AF: 0.492 Hom.: 88576

Bravo AF: 0.595

Asia WGS AF: 0.741 AC: 2577 AN: 3478

EpiCase AF: 0.447

EpiControl AF: 0.451

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.4
DANN	Benign	0.72
PhyloP100		-3.3
PromoterAI		-0.067	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Mutation Taster		=288/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs9894429; hg19: chr17-79596811; COSMIC: COSV58616438;