1-115659765-G-A

Variant names:

• chr1-115659765-G-A
• NM_138959.3:c.196G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138959.3(VANGL1):​c.196G>A​(p.Glu66Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VANGL1 NM_138959.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VANGL1	NM_138959.3	c.196G>A	p.Glu66Lys	missense_variant	Exon 3 of 8	ENST00000355485.7	NP_620409.1
VANGL1	NM_001172412.2	c.196G>A	p.Glu66Lys	missense_variant	Exon 3 of 8		NP_001165883.1
VANGL1	NM_001172411.2	c.196G>A	p.Glu66Lys	missense_variant, splice_region_variant	Exon 3 of 8		NP_001165882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VANGL1	ENST00000355485.7	c.196G>A	p.Glu66Lys	missense_variant	Exon 3 of 8	1	NM_138959.3	ENSP00000347672.2
VANGL1	ENST00000310260.7	c.196G>A	p.Glu66Lys	missense_variant	Exon 3 of 8	1		ENSP00000310800.3
VANGL1	ENST00000369509.1	c.196G>A	p.Glu66Lys	missense_variant	Exon 2 of 7	1		ENSP00000358522.1
VANGL1	ENST00000369510.8	c.196G>A	p.Glu66Lys	missense_variant, splice_region_variant	Exon 3 of 8	1		ENSP00000358523.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.196G>A (p.E66K) alteration is located in exon 3 (coding exon 2) of the VANGL1 gene. This alteration results from a G to A substitution at nucleotide position 196, causing the glutamic acid (E) at amino acid position 66 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;T;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;T;.;.
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.4	L;L;L;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Uncertain	0.50
Sift	Uncertain	0.020	D;D;D;D
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.67	P;B;P;P
Vest4		0.62
MutPred		0.60		Gain of ubiquitination at E66 (P = 0.0031);Gain of ubiquitination at E66 (P = 0.0031);Gain of ubiquitination at E66 (P = 0.0031);Gain of ubiquitination at E66 (P = 0.0031);
MVP		0.55
MPC		0.13
ClinPred		0.90	D
GERP RS		5.3
Varity_R		0.23
gMVP		0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-116202386;