rs141673853

Positions:

• chr1-115663779-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_138959.3(VANGL1):​c.323A>G​(p.Lys108Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,614,166 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: VANGL1 NM_138959.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0200

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009950548).
• BP6: Variant 1-115663779-A-G is Benign according to our data. Variant chr1-115663779-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 446031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 244 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VANGL1	NM_138959.3	c.323A>G	p.Lys108Arg	missense_variant	4/8	ENST00000355485.7
VANGL1	NM_001172412.2	c.323A>G	p.Lys108Arg	missense_variant	4/8
VANGL1	NM_001172411.2	c.317A>G	p.Lys106Arg	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VANGL1	ENST00000355485.7	c.323A>G	p.Lys108Arg	missense_variant	4/8	1	NM_138959.3	P3
VANGL1	ENST00000310260.7	c.323A>G	p.Lys108Arg	missense_variant	4/8	1		P3
VANGL1	ENST00000369509.1	c.323A>G	p.Lys108Arg	missense_variant	3/7	1		P3
VANGL1	ENST00000369510.8	c.317A>G	p.Lys106Arg	missense_variant	4/8	1		A1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.000895 AC: 225 AN: 251494 Hom.: 1 AF XY: 0.000949 AC XY: 129 AN XY: 135920

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00136 AC: 1995 AN: 1461894 Hom.: 4 Cov.: 31 AF XY: 0.00136 AC XY: 989 AN XY: 727248

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000823

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00156

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.00162 AC XY: 121 AN XY: 74472

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00771

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.00237

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000741 AC: 90

EpiCase AF: 0.00164

EpiControl AF: 0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	VANGL1: BS1, BS2 -

Sacral defect with anterior meningocele Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Neural tube defect Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.43
DANN	Benign	0.84
DEOGEN2	Benign	0.034	T;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.58	T;T;.;.
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.63	N;.;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.010	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.63	T;T;T;T
Sift4G	Benign	0.61	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.085
MVP		0.10
MPC		0.091
ClinPred		0.00021	T
GERP RS		-0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.34

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

Other links and lift over

dbSNP: rs141673853; hg19: chr1-116206400;