chr16-29833950-G-A

Position:

• chr16-29833950-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_005115.5(MVP):​c.461G>A​(p.Arg154Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000461 in 1,614,078 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: MVP NM_005115.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.408

Genes affected

MVP (HGNC:7531): (major vault protein) This gene encodes the major component of the vault complex. Vaults are multi-subunit ribonucleoprotein structures that may be involved in nucleo-cytoplasmic transport. The encoded protein may play a role in multiple cellular processes by regulating the MAP kinase, JAK/STAT and phosphoinositide 3-kinase/Akt signaling pathways. The encoded protein also plays a role in multidrug resistance, and expression of this gene may be a prognostic marker for several types of cancer. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2012]

MVP (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044409454).
• BP6: Variant 16-29833950-G-A is Benign according to our data. Variant chr16-29833950-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3151776.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MVP	NM_005115.5	c.461G>A	p.Arg154Gln	missense_variant	5/15	ENST00000357402.10	NP_005106.2
MVP	NM_017458.3	c.461G>A	p.Arg154Gln	missense_variant	5/15		NP_059447.2
MVP	NM_001293204.1	c.461G>A	p.Arg154Gln	missense_variant	4/14		NP_001280133.1
MVP	NM_001293205.1	c.461G>A	p.Arg154Gln	missense_variant	4/13		NP_001280134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MVP	ENST00000357402.10	c.461G>A	p.Arg154Gln	missense_variant	5/15	1	NM_005115.5	ENSP00000349977.5

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152132 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000509 AC: 128 AN: 251464 Hom.: 0 AF XY: 0.000625 AC XY: 85 AN XY: 135904

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000862

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000466 AC: 681 AN: 1461828 Hom.: 1 Cov.: 31 AF XY: 0.000472 AC XY: 343 AN XY: 727220

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000519

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152250 Hom.: 0 Cov.: 30 AF XY: 0.000309 AC XY: 23 AN XY: 74442

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000931 Hom.: 0

Bravo AF: 0.000442

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000519 AC: 63

EpiCase AF: 0.00104

EpiControl AF: 0.00142

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	9.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.098	T;D;D
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.85	T;T;.
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.044	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	.;L;L
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.081
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.0060	.;B;B
Vest4		0.24, 0.24
MVP		0.40
MPC		0.40
ClinPred		0.057	T
GERP RS		-3.5
Varity_R		0.060
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs144701925; hg19: chr16-29845271; COSMIC: COSV62422511; COSMIC: COSV62422511;