rs141673853

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_138959.3(VANGL1):c.323A>G(p.Lys108Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,614,166 control chromosomes in the GnomAD database, including 4 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 4 hom. )

Consequence

VANGL1
NM_138959.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0200

Publications

3 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009950548).

BP6

Variant 1-115663779-A-G is Benign according to our data. Variant chr1-115663779-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 446031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 244 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VANGL1	NM_138959.3 link	c.323A>G	p.Lys108Arg	missense_variant	Exon 4 of 8	ENST00000355485.7	NP_620409.1	Q8TAA9-1A0A024R0E3
VANGL1	NM_001172412.2 link	c.323A>G	p.Lys108Arg	missense_variant	Exon 4 of 8		NP_001165883.1	Q8TAA9-1A0A024R0E3
VANGL1	NM_001172411.2 link	c.317A>G	p.Lys106Arg	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.323A>G	p.Lys108Arg	missense_variant	Exon 4 of 8	1	NM_138959.3	ENSP00000347672.2	Q8TAA9-1
VANGL1	ENST00000310260.7 link	c.323A>G	p.Lys108Arg	missense_variant	Exon 4 of 8	1		ENSP00000310800.3	Q8TAA9-1
VANGL1	ENST00000369509.1 link	c.323A>G	p.Lys108Arg	missense_variant	Exon 3 of 7	1		ENSP00000358522.1	Q8TAA9-1
VANGL1	ENST00000369510.8 link	c.317A>G	p.Lys106Arg	missense_variant	Exon 4 of 8	1		ENSP00000358523.3	Q8TAA9-2

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

244

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00772

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00138

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.000895

AC:

225

AN:

251494

AF XY:

0.000949

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00112

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00136

AC:

1995

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

989

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000597

AC:

AN:

33480

American (AMR)

AF:

0.00163

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:

0.000823

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00156

AC:

1735

AN:

1112012

Other (OTH)

AF:

0.00147

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

145

290

435

580

725

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<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:

0.00160

AC:

244

AN:

152272

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

121

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41552

American (AMR)

AF:

0.00771

AC:

118

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00125

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00138

AC:

AN:

68018

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.00128

Hom.:

Bravo

AF:

0.00237

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000741

AC:

EpiCase

AF:

0.00164

EpiControl

AF:

0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 08, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VANGL1: BS1, BS2 -

Sacral defect with anterior meningocele

Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Neural tube defect

Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.43

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.034

T;.;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.58

T;T;.;.

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.63

N;.;N;N

PhyloP100

-0.020

PrimateAI

Benign

0.27

PROVEAN

Benign

0.010

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.63

T;T;T;T

Sift4G

Benign

0.61

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.085

MVP

0.10

MPC

0.091

ClinPred

0.00021

GERP RS

-0.33

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.025

gMVP

0.34

Mutation Taster

=100/0

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