16-4380881-T-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138440.3(VASN):c.4T>C(p.Cys2Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000329 in 1,520,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

VASN
NM_138440.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.16

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]

VASN links:

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 links:

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]

CORO7-PAM16 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04687488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VASN	NM_138440.3 link	c.4T>C	p.Cys2Arg	missense_variant	Exon 2 of 2	ENST00000304735.4	NP_612449.2	Q6EMK4
CORO7	NM_024535.5 link	c.785+7105A>G		intron_variant	Intron 9 of 27	ENST00000251166.9	NP_078811.3	P57737-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VASN	ENST00000304735.4 link	c.4T>C	p.Cys2Arg	missense_variant	Exon 2 of 2	1	NM_138440.3	ENSP00000306864.3	Q6EMK4
CORO7	ENST00000251166.9 link	c.785+7105A>G		intron_variant	Intron 9 of 27	1	NM_024535.5	ENSP00000251166.4	P57737-1
CORO7-PAM16	ENST00000572467.5 link	c.785+7105A>G		intron_variant	Intron 9 of 30	2		ENSP00000460885.1	A0A0A6YYL4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.31e-7

AC:

AN:

1368658

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

672982

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000307

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4T>C (p.C2R) alteration is located in exon 2 (coding exon 1) of the VASN gene. This alteration results from a T to C substitution at nucleotide position 4, causing the cysteine (C) at amino acid position 2 to be replaced by an arginine (R). 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

0.066

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.028

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.094

M_CAP

Benign

0.013

MetaRNN

Benign

0.047

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.80

REVEL

Benign

0.026

Sift

Pathogenic

0.0

Sift4G

Benign

0.84

Polyphen

0.0

Vest4

0.083

MutPred

0.39

Gain of methylation at C2 (P = 0.0148);

MVP

0.13

MPC

0.25

ClinPred

0.19

GERP RS

-8.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.79

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over