rs4839469

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_138959.3(VANGL1):c.346G>A(p.Ala116Thr) variant causes a missense change. The variant allele was found at a frequency of 0.147 in 1,614,090 control chromosomes in the GnomAD database, including 18,427 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1344 hom., cov: 32)

Exomes 𝑓: 0.15 ( 17083 hom. )

Consequence

VANGL1
NM_138959.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.94

Publications

40 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026085079).

BP6

Variant 1-115663802-G-A is Benign according to our data. Variant chr1-115663802-G-A is described in ClinVar as Benign. ClinVar VariationId is 292005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VANGL1	NM_138959.3 link	c.346G>A	p.Ala116Thr	missense_variant	Exon 4 of 8	ENST00000355485.7	NP_620409.1	Q8TAA9-1A0A024R0E3
VANGL1	NM_001172412.2 link	c.346G>A	p.Ala116Thr	missense_variant	Exon 4 of 8		NP_001165883.1	Q8TAA9-1A0A024R0E3
VANGL1	NM_001172411.2 link	c.340G>A	p.Ala114Thr	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.346G>A	p.Ala116Thr	missense_variant	Exon 4 of 8	1	NM_138959.3	ENSP00000347672.2	Q8TAA9-1
VANGL1	ENST00000310260.7 link	c.346G>A	p.Ala116Thr	missense_variant	Exon 4 of 8	1		ENSP00000310800.3	Q8TAA9-1
VANGL1	ENST00000369509.1 link	c.346G>A	p.Ala116Thr	missense_variant	Exon 3 of 7	1		ENSP00000358522.1	Q8TAA9-1
VANGL1	ENST00000369510.8 link	c.340G>A	p.Ala114Thr	missense_variant	Exon 4 of 8	1		ENSP00000358523.3	Q8TAA9-2

Frequencies

GnomAD3 genomes

AF:

0.127

AC:

19284

AN:

152086

Hom.:

1334

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0687

Gnomad AMI

AF:

0.216

Gnomad AMR

AF:

0.200

Gnomad ASJ

AF:

0.182

Gnomad EAS

AF:

0.120

Gnomad SAS

AF:

0.0934

Gnomad FIN

AF:

0.116

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.146

Gnomad OTH

AF:

0.145

GnomAD2 exomes

AF:

0.150

AC:

37847

AN:

251486

AF XY:

0.147

show subpopulations

Gnomad AFR exome

AF:

0.0658

Gnomad AMR exome

AF:

0.275

Gnomad ASJ exome

AF:

0.183

Gnomad EAS exome

AF:

0.119

Gnomad FIN exome

AF:

0.122

Gnomad NFE exome

AF:

0.145

Gnomad OTH exome

AF:

0.146

GnomAD4 exome

AF:

0.149

AC:

217427

AN:

1461886

Hom.:

17083

Cov.:

AF XY:

0.147

AC XY:

106864

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0642

AC:

2149

AN:

33480

American (AMR)

AF:

0.267

AC:

11945

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

4698

AN:

26136

East Asian (EAS)

AF:

0.0927

AC:

3682

AN:

39700

South Asian (SAS)

AF:

0.106

AC:

9149

AN:

86258

European-Finnish (FIN)

AF:

0.122

AC:

6505

AN:

53418

Middle Eastern (MID)

AF:

0.117

AC:

676

AN:

5768

European-Non Finnish (NFE)

AF:

0.153

AC:

169676

AN:

1112006

Other (OTH)

AF:

0.148

AC:

8947

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

13673

27345

41018

54690

68363

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6166

12332

18498

24664

30830

<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:

0.127

AC:

19291

AN:

152204

Hom.:

1344

Cov.:

AF XY:

0.125

AC XY:

9293

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0685

AC:

2846

AN:

41534

American (AMR)

AF:

0.201

AC:

3074

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.182

AC:

632

AN:

3468

East Asian (EAS)

AF:

0.120

AC:

622

AN:

5166

South Asian (SAS)

AF:

0.0929

AC:

448

AN:

4824

European-Finnish (FIN)

AF:

0.116

AC:

1225

AN:

10596

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.146

AC:

9922

AN:

68002

Other (OTH)

AF:

0.143

AC:

303

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

858

1717

2575

3434

4292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

208

416

624

832

1040

<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:

0.147

Hom.:

5891

Bravo

AF:

0.136

TwinsUK

AF:

0.159

AC:

590

ALSPAC

AF:

0.161

AC:

619

ESP6500AA

AF:

0.0679

AC:

299

ESP6500EA

AF:

0.153

AC:

1315

ExAC

AF:

0.142

AC:

17253

Asia WGS

AF:

0.122

AC:

424

AN:

3478

EpiCase

AF:

0.147

EpiControl

AF:

0.151

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21085059) -

Neural tube defect

Benign:1

Jan 12, 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. -

Sacral defect with anterior meningocele

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.088

T;.;T;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.66

T;T;.;.

MetaRNN

Benign

0.0026

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.81

L;.;L;L

PhyloP100

3.9

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.36

T;T;T;T

Sift4G

Benign

0.53

T;T;T;T

Polyphen

0.015

B;B;B;B

Vest4

0.052

MPC

0.11

ClinPred

0.0063

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.023

gMVP

0.60

Mutation Taster

=96/4

polymorphism (auto)

(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