17-81572047-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_017921.4(NPLOC4):​c.1323G>A​(p.Arg441Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,455,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R441R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NPLOC4 NM_017921.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP7: Synonymous conserved (PhyloP=-1.36 with no splicing effect.

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.1323G>A	p.Arg441Arg	synonymous	Exon 13 of 17	NP_060391.2	Q8TAT6-1
	NPLOC4	NM_001437986.1		c.1323G>A	p.Arg441Arg	synonymous	Exon 13 of 16	NP_001424915.1
	NPLOC4	NM_001369698.1		c.1338G>A	p.Arg446Arg	synonymous	Exon 13 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.1323G>A	p.Arg441Arg	synonymous	Exon 13 of 17	ENSP00000331487.5	Q8TAT6-1
	NPLOC4	ENST00000705719.1		c.1452G>A	p.Arg484Arg	synonymous	Exon 13 of 17	ENSP00000516165.1	A0A994J7H4
	NPLOC4	ENST00000374747.9	TSL:2	c.1323G>A	p.Arg441Arg	synonymous	Exon 13 of 16	ENSP00000363879.5	Q8TAT6-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1455944 Hom.: 0 Cov.: 30 AF XY: 0.00000552 AC XY: 4 AN XY: 724370

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25978

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

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53156

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

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1107970

Other (OTH) AF: 0.00 AC: 0 AN: 60034

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00229320), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	2.1
DANN	Benign	0.86
PhyloP100		-1.4
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs17852307; hg19: chr17-79539073;