chr6-132751227-A-T

Variant names:

• chr6-132751227-A-T
• rs748667023
• NM_004665.6:c.1118T>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004665.6(VNN2):​c.1118T>A​(p.Met373Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: VNN2 NM_004665.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.55

Genes affected

VNN2 (HGNC:12706): (vanin 2) This gene product is a member of the Vanin family of proteins that 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. The encoded protein is a GPI-anchored cell surface molecule that plays a role in transendothelial migration of neutrophils. This gene lies in close proximity to, and in same transcriptional orientation as two other vanin genes on chromosome 6q23-q24. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, May 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VNN2	NM_004665.6	c.1118T>A	p.Met373Lys	missense_variant	Exon 5 of 7	ENST00000326499.11	NP_004656.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VNN2	ENST00000326499.11	c.1118T>A	p.Met373Lys	missense_variant	Exon 5 of 7	1	NM_004665.6	ENSP00000322276.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251118 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135718

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1118T>A (p.M373K) alteration is located in exon 5 (coding exon 5) of the VNN2 gene. This alteration results from a T to A substitution at nucleotide position 1118, causing the methionine (M) at amino acid position 373 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Benign	0.054	T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.73	T;T
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.0067	D
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	D;N
REVEL	Uncertain	0.64
Sift	Benign	0.67	T;T
Sift4G	Benign	0.84	T;T
Polyphen		0.28	B;.
Vest4		0.76
MutPred		0.61		Gain of ubiquitination at M373 (P = 0.0101);.;
MVP		0.59
MPC		0.067
ClinPred		0.29	T
GERP RS		4.5
Varity_R		0.19
gMVP		0.87

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: rs748667023; hg19: chr6-133072366;