NM_138959.3:c.323A>G

Variant names:

• chr1-115663779-A-G
• rs141673853
• NM_138959.3:c.323A>G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 446031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 244 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VANGL1	NM_138959.3	MANE Select	c.323A>G	p.Lys108Arg	missense	Exon 4 of 8	NP_620409.1	Q8TAA9-1
	VANGL1	NM_001172412.2		c.323A>G	p.Lys108Arg	missense	Exon 4 of 8	NP_001165883.1	Q8TAA9-1
	VANGL1	NM_001172411.2		c.317A>G	p.Lys106Arg	missense	Exon 4 of 8	NP_001165882.1	Q8TAA9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VANGL1	ENST00000355485.7	TSL:1 MANE Select	c.323A>G	p.Lys108Arg	missense	Exon 4 of 8	ENSP00000347672.2	Q8TAA9-1
	VANGL1	ENST00000310260.7	TSL:1	c.323A>G	p.Lys108Arg	missense	Exon 4 of 8	ENSP00000310800.3	Q8TAA9-1
	VANGL1	ENST00000369509.1	TSL:1	c.323A>G	p.Lys108Arg	missense	Exon 3 of 7	ENSP00000358522.1	Q8TAA9-1

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

GnomAD2 exomes AF: 0.000895 AC: 225 AN: 251494 AF XY: 0.000949

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 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

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.00163 AC: 73 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000823 AC: 71 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00156 AC: 1735 AN: 1112012

Other (OTH) AF: 0.00147 AC: 89 AN: 60396

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

African (AFR) AF: 0.000409 AC: 17 AN: 41552

American (AMR) AF: 0.00771 AC: 118 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00138 AC: 94 AN: 68018

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00128 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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Neural tube defect (1)
-	-	1	Sacral defect with anterior meningocele (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.63	N
PhyloP100		-0.020
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.14
Sift	Benign	0.63	T
Sift4G	Benign	0.61	T
Polyphen		0.0	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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs141673853; hg19: chr1-116206400;