rs139070771

Variant names:

• chr1-224227651-C-A
• rs139070771
• NM_002533.4:c.2546G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-224227651-C-A
• chr1-224227651-C-T

Variant summary

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

The NM_002533.4(NVL):​c.2546G>T​(p.Arg849Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/24 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R849C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NVL NM_002533.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.122
• Publications: 0 publications found

Genes affected

NVL (HGNC:8070): (nuclear VCP like) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) superfamily. Multiple transcript variants encoding different isoforms have been found for this gene. Two encoded proteins, described as major and minor isoforms, have been localized to distinct regions of the nucleus. The largest encoded protein (major isoform) has been localized to the nucleolus and shown to participate in ribosome biosynthesis (PMID: 15469983, 16782053), while the minor isoform has been localized to the nucleoplasmin. [provided by RefSeq, Aug 2011]

ENSG00000237101 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002533.4. 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
	NVL	NM_002533.4	MANE Select	c.2546G>T	p.Arg849Leu	missense	Exon 23 of 23	NP_002524.2
	NVL	NM_001243147.2		c.2273G>T	p.Arg758Leu	missense	Exon 22 of 22	NP_001230076.1	O15381-5
	NVL	NM_206840.3		c.2228G>T	p.Arg743Leu	missense	Exon 22 of 22	NP_996671.1	O15381-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NVL	ENST00000281701.11	TSL:1 MANE Select	c.2546G>T	p.Arg849Leu	missense	Exon 23 of 23	ENSP00000281701.6	O15381-1
	NVL	ENST00000391875.6	TSL:1	c.2228G>T	p.Arg743Leu	missense	Exon 22 of 22	ENSP00000375747.2	O15381-2
	ENSG00000237101	ENST00000420350.1	TSL:1	n.931C>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.12
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.28
Sift	Benign	0.14	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.37		Loss of MoRF binding (P = 8e-04)
MVP		0.92
MPC		0.33
ClinPred		0.15	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
gMVP		0.23
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.48		Position offset: -8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139070771; hg19: chr1-224415353;