rs4839469

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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:3

Conservation

PhyloP100: 3.94

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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/exons	MANE
VANGL1	NM_138959.3 linkuse as main transcript	c.346G>A	p.Ala116Thr	missense_variant	4/8	ENST00000355485.7
VANGL1	NM_001172412.2 linkuse as main transcript	c.346G>A	p.Ala116Thr	missense_variant	4/8
VANGL1	NM_001172411.2 linkuse as main transcript	c.340G>A	p.Ala114Thr	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VANGL1	ENST00000355485.7 linkuse as main transcript	c.346G>A	p.Ala116Thr	missense_variant	4/8	1	NM_138959.3	P3	Q8TAA9-1
VANGL1	ENST00000310260.7 linkuse as main transcript	c.346G>A	p.Ala116Thr	missense_variant	4/8	1		P3	Q8TAA9-1
VANGL1	ENST00000369509.1 linkuse as main transcript	c.346G>A	p.Ala116Thr	missense_variant	3/7	1		P3	Q8TAA9-1
VANGL1	ENST00000369510.8 linkuse as main transcript	c.340G>A	p.Ala114Thr	missense_variant	4/8	1		A1	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

GnomAD3 exomes

AF:

0.150

AC:

37847

AN:

251486

Hom.:

3383

AF XY:

0.147

AC XY:

20005

AN XY:

135914

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 SAS exome

AF:

0.105

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

Gnomad4 AFR exome

AF:

0.0642

Gnomad4 AMR exome

AF:

0.267

Gnomad4 ASJ exome

AF:

0.180

Gnomad4 EAS exome

AF:

0.0927

Gnomad4 SAS exome

AF:

0.106

Gnomad4 FIN exome

AF:

0.122

Gnomad4 NFE exome

AF:

0.153

Gnomad4 OTH exome

AF:

0.148

GnomAD4 genome

AF:

0.127

AC:

19291

AN:

152204

Hom.:

1344

Cov.:

AF XY:

0.125

AC XY:

9293

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0685

Gnomad4 AMR

AF:

0.201

Gnomad4 ASJ

AF:

0.182

Gnomad4 EAS

AF:

0.120

Gnomad4 SAS

AF:

0.0929

Gnomad4 FIN

AF:

0.116

Gnomad4 NFE

AF:

0.146

Gnomad4 OTH

AF:

0.143

Alfa

AF:

0.148

Hom.:

4341

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

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

Neural tube defect

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

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

MutationTaster

Benign

0.82

P;P;P;P

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

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.

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