1-115664171-G-A

Position:

chr1-115664171-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_138959.3(VANGL1):c.715G>A(p.Val239Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000434 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

VANGL1
NM_138959.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:2

Conservation

PhyloP100: 5.59

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23214778).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VANGL1	NM_138959.3 linkuse as main transcript	c.715G>A	p.Val239Ile	missense_variant	4/8	ENST00000355485.7
VANGL1	NM_001172412.2 linkuse as main transcript	c.715G>A	p.Val239Ile	missense_variant	4/8
VANGL1	NM_001172411.2 linkuse as main transcript	c.709G>A	p.Val237Ile	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VANGL1	ENST00000355485.7 linkuse as main transcript	c.715G>A	p.Val239Ile	missense_variant	4/8	1	NM_138959.3	P3	Q8TAA9-1
VANGL1	ENST00000310260.7 linkuse as main transcript	c.715G>A	p.Val239Ile	missense_variant	4/8	1		P3	Q8TAA9-1
VANGL1	ENST00000369509.1 linkuse as main transcript	c.715G>A	p.Val239Ile	missense_variant	3/7	1		P3	Q8TAA9-1
VANGL1	ENST00000369510.8 linkuse as main transcript	c.709G>A	p.Val237Ile	missense_variant	4/8	1		A1	Q8TAA9-2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

250772

Hom.:

AF XY:

0.0000738

AC XY:

AN XY:

135554

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1461778

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The VANGL1 p.V239I variant was identified in 1 of 288 proband chromosomes (frequency: 0.0034) from individuals or families with caudal regression and was not identified in 212 control chromosomes from healthy individuals (Kibar_2007_PMID:17409324). The variant was identified in dbSNP (ID: rs121918218) and ClinVar (classified as likely pathogenic in 2016 by GeneDx). The variant was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 17 of 282170 chromosomes (0 homozygous) at a frequency of 0.00006025 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 15 of 128536 chromosomes (freq: 0.000117), East Asian in 1 of 19952 chromosomes (freq: 0.00005) and African in 1 of 24968 chromosomes (freq: 0.00004), but was not observed in the Latino, Ashkenazi Jewish, European (Finnish), Other or South Asian populations. The p.Val239Ile variant was identified in a 10-year-old Italian girl who had a severe form of caudal regression and was also found in her brother who had a milder form of the disease, dermal sinus (Kibar_2007_PMID:17409324). However, the variant was also found in their unaffected mother, suggesting incomplete penetrance or variable expressivity (Kibar_2007_PMID:17409324). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Val239 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. However, in a protein-protein interaction assay the p.V239I variant was found to have a deleterious affect on the protein, abolishing interaction of the VANGL1 protein with its binding partners (Kibar_2007_PMID:17409324). In a zebrafish model, knockdown/rescue experiments and overexpression assays suggested that the p.V239I variant results in a loss of function allele that affects protein function during embryonic development (Reynolds_2010_PMID: 20043994). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2023	Published functional studies of V239I indicate that it inhibits the interaction of VANGL1 with Dvl proteins, potentially inhibiting molecular signaling during gastrulation and neural-tube closure (Kibar et al., 2007; Renolds et al., 2010); Identified in an individual with caudal regression with lipomyeloschisis, anorectal malformation, hydromyelia, and a tethered spinal cord. The V239I variant was also present in her unaffected mother and mildly affected brother who had dermal sinus (Kibar et al., 2007); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25208524, 17409324, 31589614, 20043994) -

Caudal regression sequence

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 05, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;.;T;T

Eigen

Benign

-0.18

Eigen_PC

Benign

0.011

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

T;T;.;.

M_CAP

Benign

0.028

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.5

L;.;L;L

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.25

N;N;N;N

REVEL

Uncertain

0.46

Sift

Benign

0.35

T;T;T;T

Sift4G

Benign

0.45

T;T;T;T

Polyphen

0.13

B;B;B;B

Vest4

0.25

MVP

0.95

MPC

0.11

ClinPred

0.31

GERP RS

4.8

Varity_R

0.039

gMVP

0.35

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