16-4381371-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_138440.3(VASN):​c.494C>T​(p.Pro165Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,591,792 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

VASN
NM_138440.3 missense

Scores

4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.15
Variant links:
Genes affected
VASN (HGNC:18517): (vasorin) Enables transforming growth factor beta binding activity. Involved in negative regulation of epithelial to mesenchymal transition and negative regulation of transforming growth factor beta receptor signaling pathway. Located in cell surface and extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]
CORO7 (HGNC:26161): (coronin 7) This gene encodes a member of the coronin protein family. However, unlike other coronin proteins, it is not an actin-binding protein but rather functions as an F-actin regulator directing anterograde Golgi to endosome transport. The encoded protein has two tandem WD-40 domain repeats and localizes to the trans-Golgi network. The protein undergoes K33-linked polyubiquitination via an E3 ligase complex. It is thought to play an essential role in maintenance of Golgi apparatus morphology. Alternative splicing results in multiple transcripts variants; some of which form read-through transcripts with a neighboring gene. [provided by RefSeq, Dec 2016]
CORO7-PAM16 (HGNC:44424): (CORO7-PAM16 readthrough) This locus represents naturally occurring read-through transcription between the neighboring CORO7 (coronin 7) and PAM16 (presequence translocase-associated motor 16) genes on chromosome 16. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Jan 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1568732).
BS2
High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VASNNM_138440.3 linkc.494C>T p.Pro165Leu missense_variant 2/2 ENST00000304735.4 NP_612449.2 Q6EMK4
CORO7NM_024535.5 linkc.785+6615G>A intron_variant ENST00000251166.9 NP_078811.3 P57737-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VASNENST00000304735.4 linkc.494C>T p.Pro165Leu missense_variant 2/21 NM_138440.3 ENSP00000306864.3 Q6EMK4
CORO7ENST00000251166.9 linkc.785+6615G>A intron_variant 1 NM_024535.5 ENSP00000251166.4 P57737-1
CORO7-PAM16ENST00000572467.5 linkc.785+6615G>A intron_variant 2 ENSP00000460885.1 A0A0A6YYL4

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152250
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000148
AC:
3
AN:
203178
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
111992
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000326
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000685
Gnomad SAS exome
AF:
0.0000367
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000146
AC:
21
AN:
1439542
Hom.:
0
Cov.:
116
AF XY:
0.0000140
AC XY:
10
AN XY:
714998
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000238
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000529
Gnomad4 SAS exome
AF:
0.0000119
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000154
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152250
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 23, 2024The c.494C>T (p.P165L) alteration is located in exon 2 (coding exon 1) of the VASN gene. This alteration results from a C to T substitution at nucleotide position 494, causing the proline (P) at amino acid position 165 to be replaced by a leucine (L). 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
0.093
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
20
DANN
Benign
0.97
DEOGEN2
Benign
0.081
T
Eigen
Benign
-0.71
Eigen_PC
Benign
-0.57
FATHMM_MKL
Uncertain
0.79
D
M_CAP
Uncertain
0.14
D
MetaRNN
Benign
0.16
T
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
1.2
L
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.2
N
REVEL
Benign
0.16
Sift
Benign
0.045
D
Sift4G
Uncertain
0.020
D
Polyphen
0.14
B
Vest4
0.23
MutPred
0.47
Loss of catalytic residue at P164 (P = 0.0215);
MVP
0.81
MPC
0.073
ClinPred
0.085
T
GERP RS
3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.044
gMVP
0.52

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1361259040; hg19: chr16-4431372; API