Genetic Variant NM_138959.3:c.-115G>C (chr1-115651299-G-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_138959.3(VANGL1):c.-115G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000442 in 837,136 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 2 hom. )

Consequence

VANGL1
NM_138959.3 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.0800

Publications

0 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 1-115651299-G-C is Benign according to our data. Variant chr1-115651299-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 292001.

BS2

High AC in GnomAd4 at 56 AD gene.

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	Effect	Exon Rank	Protein	UniProt
VANGL1	NM_138959.3	MANE Select	c.-115G>C	5_prime_UTR	Exon 2 of 8	NP_620409.1	Q8TAA9-1
VANGL1	NM_001172412.2		c.-115G>C	5_prime_UTR	Exon 2 of 8	NP_001165883.1	Q8TAA9-1
VANGL1	NM_001172411.2		c.-115G>C	5_prime_UTR	Exon 2 of 8	NP_001165882.1	Q8TAA9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VANGL1	ENST00000355485.7	TSL:1 MANE Select	c.-115G>C	5_prime_UTR	Exon 2 of 8	ENSP00000347672.2	Q8TAA9-1
VANGL1	ENST00000310260.7	TSL:1	c.-115G>C	5_prime_UTR	Exon 2 of 8	ENSP00000310800.3	Q8TAA9-1
VANGL1	ENST00000369510.8	TSL:1	c.-115G>C	5_prime_UTR	Exon 2 of 8	ENSP00000358523.3	Q8TAA9-2

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0104

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000458

AC:

314

AN:

685028

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

161

AN XY:

362734

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17438

American (AMR)

AF:

0.00

AC:

AN:

33232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20428

East Asian (EAS)

AF:

0.00868

AC:

285

AN:

32824

South Asian (SAS)

AF:

0.000174

AC:

AN:

63316

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39006

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4258

European-Non Finnish (NFE)

AF:

0.00000682

AC:

AN:

439868

Other (OTH)

AF:

0.000433

AC:

AN:

34658

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000368

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41492

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0104

AC:

AN:

5184

South Asian (SAS)

AF:

0.000208

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67990

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.000684

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neural tube defect (1)

Sacral defect with anterior meningocele (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

3.3

(source)

DANN

Benign

0.44

PhyloP100

0.080

PromoterAI

-0.0024

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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