rs4839469

Variant names:

• chr1-115663802-G-A
• rs4839469
• NM_138959.3:c.346G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-115663802-G-A
• chr1-115663802-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138959.3(VANGL1):​c.346G>A​(p.Ala116Thr) variant causes a missense change. The variant allele was found at a frequency of 0.147 in 1,614,090 control chromosomes in the GnomAD database, including 18,427 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1344 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17083 hom.)
• Consequence: VANGL1 NM_138959.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.94
• Publications: 40 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026085079).
• BP6: Variant 1-115663802-G-A is Benign according to our data. Variant chr1-115663802-G-A is described in ClinVar as Benign. ClinVar VariationId is 292005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.195 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VANGL1	NM_138959.3	MANE Select	c.346G>A	p.Ala116Thr	missense	Exon 4 of 8	NP_620409.1	Q8TAA9-1
	VANGL1	NM_001172412.2		c.346G>A	p.Ala116Thr	missense	Exon 4 of 8	NP_001165883.1	Q8TAA9-1
	VANGL1	NM_001172411.2		c.340G>A	p.Ala114Thr	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.346G>A	p.Ala116Thr	missense	Exon 4 of 8	ENSP00000347672.2	Q8TAA9-1
	VANGL1	ENST00000310260.7	TSL:1	c.346G>A	p.Ala116Thr	missense	Exon 4 of 8	ENSP00000310800.3	Q8TAA9-1
	VANGL1	ENST00000369509.1	TSL:1	c.346G>A	p.Ala116Thr	missense	Exon 3 of 7	ENSP00000358522.1	Q8TAA9-1

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19284 AN: 152086 Hom.: 1334 Cov.: 32

Gnomad AFR AF: 0.0687

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0934

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.145

GnomAD2 exomes AF: 0.150 AC: 37847 AN: 251486 AF XY: 0.147

Gnomad AFR exome AF: 0.0658

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.119

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.149 AC: 217427 AN: 1461886 Hom.: 17083 Cov.: 33 AF XY: 0.147 AC XY: 106864 AN XY: 727244

African (AFR) AF: 0.0642 AC: 2149 AN: 33480

American (AMR) AF: 0.267 AC: 11945 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4698 AN: 26136

East Asian (EAS) AF: 0.0927 AC: 3682 AN: 39700

South Asian (SAS) AF: 0.106 AC: 9149 AN: 86258

European-Finnish (FIN) AF: 0.122 AC: 6505 AN: 53418

Middle Eastern (MID) AF: 0.117 AC: 676 AN: 5768

European-Non Finnish (NFE) AF: 0.153 AC: 169676 AN: 1112006

Other (OTH) AF: 0.148 AC: 8947 AN: 60396

GnomAD4 genome AF: 0.127 AC: 19291 AN: 152204 Hom.: 1344 Cov.: 32 AF XY: 0.125 AC XY: 9293 AN XY: 74426

African (AFR) AF: 0.0685 AC: 2846 AN: 41534

American (AMR) AF: 0.201 AC: 3074 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 632 AN: 3468

East Asian (EAS) AF: 0.120 AC: 622 AN: 5166

South Asian (SAS) AF: 0.0929 AC: 448 AN: 4824

European-Finnish (FIN) AF: 0.116 AC: 1225 AN: 10596

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9922 AN: 68002

Other (OTH) AF: 0.143 AC: 303 AN: 2112

Alfa AF: 0.147 Hom.: 5891

Bravo AF: 0.136

TwinsUK AF: 0.159 AC: 590

ALSPAC AF: 0.161 AC: 619

ESP6500AA AF: 0.0679 AC: 299

ESP6500EA AF: 0.153 AC: 1315

ExAC AF: 0.142 AC: 17253

Asia WGS AF: 0.122 AC: 424 AN: 3478

EpiCase AF: 0.147

EpiControl AF: 0.151

ClinVar

ClinVar submissions

Significance: 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	0.095
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.81	L
PhyloP100		3.9
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Benign	0.36	T
Sift4G	Benign	0.53	T
Polyphen		0.015	B
Vest4		0.052
MPC		0.11
ClinPred		0.0063	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.023
gMVP		0.60
Mutation Taster		=96/4	polymorphism (auto)

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: rs4839469; hg19: chr1-116206423; COSMIC: COSV59619891;