rs2272996

Positions:

• chr6-132694132-T-A
• chr6-132694132-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004666.3(VNN1):​c.392A>T​(p.Asn131Ile) 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 pathogenic 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. N131S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VNN1 NM_004666.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.83

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VNN1	NM_004666.3	c.392A>T	p.Asn131Ile	missense_variant	3/7	ENST00000367928.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VNN1	ENST00000367928.5	c.392A>T	p.Asn131Ile	missense_variant	3/7	1	NM_004666.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	0.0025	P
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.57		Gain of sheet (P = 0.0827);
MVP		0.96
MPC		0.28
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.96
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs2272996; hg19: chr6-133015271;