Genetic Variant VANGL1:p.Ala116Pro (chr1-115663802-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_138959.3(VANGL1):c.346G>C(p.Ala116Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A116T) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

VANGL1
NM_138959.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
VANGL1	NM_138959.3 link	c.346G>C	p.Ala116Pro	missense_variant	Exon 4 of 8	ENST00000355485.7	NP_620409.1
VANGL1	NM_001172412.2 link	c.346G>C	p.Ala116Pro	missense_variant	Exon 4 of 8		NP_001165883.1
VANGL1	NM_001172411.2 link	c.340G>C	p.Ala114Pro	missense_variant	Exon 4 of 8		NP_001165882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
VANGL1	ENST00000355485.7 link	c.346G>C	p.Ala116Pro	missense_variant	Exon 4 of 8	1	NM_138959.3	ENSP00000347672.2
VANGL1	ENST00000310260.7 link	c.346G>C	p.Ala116Pro	missense_variant	Exon 4 of 8	1		ENSP00000310800.3
VANGL1	ENST00000369509.1 link	c.346G>C	p.Ala116Pro	missense_variant	Exon 3 of 7	1		ENSP00000358522.1
VANGL1	ENST00000369510.8 link	c.340G>C	p.Ala114Pro	missense_variant	Exon 4 of 8	1		ENSP00000358523.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;.;T;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.71

T;T;.;.

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.0

M;.;M;M

PhyloP100

3.9

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.0

D;D;D;D

REVEL

Uncertain

0.53

Sift

Benign

0.058

T;T;T;T

Sift4G

Uncertain

0.051

T;T;T;T

Polyphen

0.0040

B;B;B;B

Vest4

0.83

MutPred

0.71

Loss of helix (P = 0.0068);.;Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);

MVP

0.99

MPC

0.15

ClinPred

0.78

GERP RS

3.9

Varity_R

0.46

gMVP

0.90

Mutation Taster

=74/26

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over