Genetic Variant VNN1:p.Asn131Ser (chr6-132694132-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004666.3(VNN1):c.392A>G(p.Asn131Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,613,480 control chromosomes in the GnomAD database, including 59,470 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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.24 ( 4693 hom., cov: 32)

Exomes 𝑓: 0.27 ( 54777 hom. )

Consequence

VNN1
NM_004666.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.83

Variant links:

Genes affected

VNN1 (HGNC:12705): (vanin 1) This gene encodes a member of the vanin family of proteins, which share extensive sequence similarity with each other, and also with biotinidase. The family includes secreted and membrane-associated proteins, a few of which have been reported to participate in hematopoietic cell trafficking. No biotinidase activity has been demonstrated for any of the vanin proteins, however, they possess pantetheinase activity, which may play a role in oxidative-stress response. This protein, like its mouse homolog, is likely a GPI-anchored cell surface molecule. The mouse protein is expressed by the perivascular thymic stromal cells and regulates migration of T-cell progenitors to the thymus. This gene lies in close proximity to, and in the same transcriptional orientation as, two other vanin genes on chromosome 6q23-q24. [provided by RefSeq, Feb 2009]

VNN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035597682).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VNN1	NM_004666.3 link	c.392A>G	p.Asn131Ser	missense_variant	Exon 3 of 7	ENST00000367928.5	NP_004657.2	O95497

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VNN1	ENST00000367928.5 link	c.392A>G	p.Asn131Ser	missense_variant	Exon 3 of 7	1	NM_004666.3	ENSP00000356905.4		O95497

Frequencies

GnomAD3 genomes

AF:

0.241

AC:

36609

AN:

151870

Hom.:

4699

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.229

Gnomad AMR

AF:

0.180

Gnomad ASJ

AF:

0.278

Gnomad EAS

AF:

0.379

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.275

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.264

Gnomad OTH

AF:

0.228

GnomAD2 exomes

AF:

0.266

AC:

66628

AN:

250754

AF XY:

0.271

show subpopulations

Gnomad AFR exome

AF:

0.189

Gnomad AMR exome

AF:

0.179

Gnomad ASJ exome

AF:

0.262

Gnomad EAS exome

AF:

0.388

Gnomad FIN exome

AF:

0.273

Gnomad NFE exome

AF:

0.274

Gnomad OTH exome

AF:

0.253

GnomAD4 exome

AF:

0.271

AC:

395397

AN:

1461492

Hom.:

54777

Cov.:

AF XY:

0.271

AC XY:

196986

AN XY:

727022

show subpopulations

African (AFR)

AF:

0.184

AC:

6162

AN:

33474

American (AMR)

AF:

0.179

AC:

7977

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.265

AC:

6917

AN:

26112

East Asian (EAS)

AF:

0.405

AC:

16065

AN:

39684

South Asian (SAS)

AF:

0.294

AC:

25323

AN:

86194

European-Finnish (FIN)

AF:

0.276

AC:

14723

AN:

53410

Middle Eastern (MID)

AF:

0.211

AC:

1215

AN:

5766

European-Non Finnish (NFE)

AF:

0.271

AC:

301172

AN:

1111784

Other (OTH)

AF:

0.262

AC:

15843

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

15863

31726

47590

63453

79316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.241

AC:

36609

AN:

151988

Hom.:

4693

Cov.:

AF XY:

0.242

AC XY:

17964

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.191

AC:

7933

AN:

41438

American (AMR)

AF:

0.180

AC:

2746

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.278

AC:

962

AN:

3466

East Asian (EAS)

AF:

0.379

AC:

1959

AN:

5174

South Asian (SAS)

AF:

0.296

AC:

1427

AN:

4824

European-Finnish (FIN)

AF:

0.275

AC:

2906

AN:

10552

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.264

AC:

17916

AN:

67968

Other (OTH)

AF:

0.227

AC:

480

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1443

2885

4328

5770

7213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.249

Hom.:

2198

Bravo

AF:

0.233

TwinsUK

AF:

0.265

AC:

983

ALSPAC

AF:

0.269

AC:

1036

ESP6500AA

AF:

0.191

AC:

840

ESP6500EA

AF:

0.270

AC:

2320

ExAC

AF:

0.272

AC:

32968

Asia WGS

AF:

0.298

AC:

1035

AN:

3478

EpiCase

AF:

0.269

EpiControl

AF:

0.265

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0036

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.8

PhyloP100

2.8

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.34

Sift

Benign

0.034

Sift4G

Benign

0.17

Polyphen

1.0

Vest4

0.24

MPC

0.23

ClinPred

0.028

GERP RS

6.1

Varity_R

0.60

gMVP

0.58

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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6-132694132-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over