Genetic Variant NM_138959.3:c.1040A>C (chr1-115684037-A-C) – ACMG Classification: Benign (-20 pts)

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.1040A>C(p.Glu347Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,614,124 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 57 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 55 hom. )

Consequence

VANGL1
NM_138959.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.94

Publications

9 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=0.009638548).

BP6

Variant 1-115684037-A-C is Benign according to our data. Variant chr1-115684037-A-C is described in ClinVar as Benign. ClinVar VariationId is 292011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138959.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VANGL1	NM_138959.3	MANE Select	c.1040A>C	p.Glu347Ala	missense	Exon 6 of 8	NP_620409.1
VANGL1	NM_001172412.2		c.1040A>C	p.Glu347Ala	missense	Exon 6 of 8	NP_001165883.1
VANGL1	NM_001172411.2		c.1034A>C	p.Glu345Ala	missense	Exon 6 of 8	NP_001165882.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VANGL1	ENST00000355485.7	TSL:1 MANE Select	c.1040A>C	p.Glu347Ala	missense	Exon 6 of 8	ENSP00000347672.2
VANGL1	ENST00000310260.7	TSL:1	c.1040A>C	p.Glu347Ala	missense	Exon 6 of 8	ENSP00000310800.3
VANGL1	ENST00000369509.1	TSL:1	c.1040A>C	p.Glu347Ala	missense	Exon 5 of 7	ENSP00000358522.1

Frequencies

GnomAD3 genomes

AF:

0.0155

AC:

2357

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0545

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00451

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00398

AC:

1001

AN:

251492

AF XY:

0.00293

show subpopulations

Gnomad AFR exome

AF:

0.0538

Gnomad AMR exome

AF:

0.00280

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00157

AC:

2292

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

979

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0562

AC:

1881

AN:

33478

American (AMR)

AF:

0.00318

AC:

142

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000139

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000423

AC:

AN:

1111964

Other (OTH)

AF:

0.00333

AC:

201

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

129

258

386

515

644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.0155

AC:

2364

AN:

152322

Hom.:

Cov.:

AF XY:

0.0151

AC XY:

1124

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0545

AC:

2266

AN:

41560

American (AMR)

AF:

0.00451

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68036

Other (OTH)

AF:

0.00851

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

123

246

368

491

614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00569

Hom.:

Bravo

AF:

0.0174

ESP6500AA

AF:

0.0490

AC:

216

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00460

AC:

559

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Neural tube defect (1)

Sacral defect with anterior meningocele (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0096

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

1.8

PhyloP100

8.9

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.89

Vest4

0.83

MVP

0.56

MPC

0.47

ClinPred

0.040

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.77

gMVP

0.70

Mutation Taster

=94/6

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over