NM_138959.3:c.523C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_138959.3(VANGL1):c.523C>T(p.Arg175Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000634 in 1,614,184 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00057 ( 1 hom. )

Consequence

VANGL1
NM_138959.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.40

Publications

7 publications found

Variant links:

Genes affected

VANGL1 (HGNC:15512): (VANGL planar cell polarity protein 1) This gene encodes a member of the tretraspanin family. The encoded protein may be involved in mediating intestinal trefoil factor induced wound healing in the intestinal mucosa. Mutations in this gene are associated with neural tube defects. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]

VANGL1 Gene-Disease associations (from GenCC):

neural tube defects, susceptibility to
Inheritance: AD Classification: LIMITED Submitted by: G2P

VANGL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009320825).

BP6

Variant 1-115663979-C-T is Benign according to our data. Variant chr1-115663979-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167818.

BS2

High AC in GnomAd4 at 186 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VANGL1	NM_138959.3 link	c.523C>T	p.Arg175Trp	missense_variant	Exon 4 of 8	ENST00000355485.7	NP_620409.1	Q8TAA9-1A0A024R0E3
VANGL1	NM_001172412.2 link	c.523C>T	p.Arg175Trp	missense_variant	Exon 4 of 8		NP_001165883.1	Q8TAA9-1A0A024R0E3
VANGL1	NM_001172411.2 link	c.517C>T	p.Arg173Trp	missense_variant	Exon 4 of 8		NP_001165882.1	Q8TAA9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VANGL1	ENST00000355485.7 link	c.523C>T	p.Arg175Trp	missense_variant	Exon 4 of 8	1	NM_138959.3	ENSP00000347672.2	Q8TAA9-1
VANGL1	ENST00000310260.7 link	c.523C>T	p.Arg175Trp	missense_variant	Exon 4 of 8	1		ENSP00000310800.3	Q8TAA9-1
VANGL1	ENST00000369509.1 link	c.523C>T	p.Arg175Trp	missense_variant	Exon 3 of 7	1		ENSP00000358522.1	Q8TAA9-1
VANGL1	ENST00000369510.8 link	c.517C>T	p.Arg173Trp	missense_variant	Exon 4 of 8	1		ENSP00000358523.3	Q8TAA9-2

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

186

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000585

AC:

147

AN:

251494

AF XY:

0.000412

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000431

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000573

AC:

838

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000542

AC XY:

394

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00314

AC:

105

AN:

33480

American (AMR)

AF:

0.00127

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000536

AC:

596

AN:

1112012

Other (OTH)

AF:

0.000861

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

111

167

222

278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00122

AC:

186

AN:

152290

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00322

AC:

134

AN:

41568

American (AMR)

AF:

0.000981

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68018

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000730

Hom.:

Bravo

AF:

0.00127

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000576

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Nov 19, 2018

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 17, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neural tube defect

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Sacral defect with anterior meningocele

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

D;.;D;D

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.97

D;D;.;.

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.0093

T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.4

L;.;L;L

PhyloP100

1.4

PrimateAI

Benign

0.23

PROVEAN

Benign

-2.2

N;N;N;N

REVEL

Uncertain

0.30

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.012

D;D;D;D

Polyphen

0.98

D;D;D;D

Vest4

0.23

MVP

0.25

MPC

0.27

ClinPred

0.010

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.092

gMVP

0.51

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over