1-115664171-G-A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_138959.3(VANGL1):c.715G>A(p.Val239Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000434 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_138959.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VANGL1 | NM_138959.3 | c.715G>A | p.Val239Ile | missense_variant | Exon 4 of 8 | ENST00000355485.7 | NP_620409.1 | |
VANGL1 | NM_001172412.2 | c.715G>A | p.Val239Ile | missense_variant | Exon 4 of 8 | NP_001165883.1 | ||
VANGL1 | NM_001172411.2 | c.709G>A | p.Val237Ile | missense_variant | Exon 4 of 8 | NP_001165882.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VANGL1 | ENST00000355485.7 | c.715G>A | p.Val239Ile | missense_variant | Exon 4 of 8 | 1 | NM_138959.3 | ENSP00000347672.2 | ||
VANGL1 | ENST00000310260.7 | c.715G>A | p.Val239Ile | missense_variant | Exon 4 of 8 | 1 | ENSP00000310800.3 | |||
VANGL1 | ENST00000369509.1 | c.715G>A | p.Val239Ile | missense_variant | Exon 3 of 7 | 1 | ENSP00000358522.1 | |||
VANGL1 | ENST00000369510.8 | c.709G>A | p.Val237Ile | missense_variant | Exon 4 of 8 | 1 | ENSP00000358523.3 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000518 AC: 13AN: 250772Hom.: 0 AF XY: 0.0000738 AC XY: 10AN XY: 135554
GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461778Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 35AN XY: 727166
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74330
ClinVar
Submissions by phenotype
not provided Uncertain:2
The VANGL1 p.V239I variant was identified in 1 of 288 proband chromosomes (frequency: 0.0034) from individuals or families with caudal regression and was not identified in 212 control chromosomes from healthy individuals (Kibar_2007_PMID:17409324). The variant was identified in dbSNP (ID: rs121918218) and ClinVar (classified as likely pathogenic in 2016 by GeneDx). The variant was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 17 of 282170 chromosomes (0 homozygous) at a frequency of 0.00006025 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 15 of 128536 chromosomes (freq: 0.000117), East Asian in 1 of 19952 chromosomes (freq: 0.00005) and African in 1 of 24968 chromosomes (freq: 0.00004), but was not observed in the Latino, Ashkenazi Jewish, European (Finnish), Other or South Asian populations. The p.Val239Ile variant was identified in a 10-year-old Italian girl who had a severe form of caudal regression and was also found in her brother who had a milder form of the disease, dermal sinus (Kibar_2007_PMID:17409324). However, the variant was also found in their unaffected mother, suggesting incomplete penetrance or variable expressivity (Kibar_2007_PMID:17409324). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Val239 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. However, in a protein-protein interaction assay the p.V239I variant was found to have a deleterious affect on the protein, abolishing interaction of the VANGL1 protein with its binding partners (Kibar_2007_PMID:17409324). In a zebrafish model, knockdown/rescue experiments and overexpression assays suggested that the p.V239I variant results in a loss of function allele that affects protein function during embryonic development (Reynolds_2010_PMID: 20043994). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Published functional studies of V239I indicate that it inhibits the interaction of VANGL1 with Dvl proteins, potentially inhibiting molecular signaling during gastrulation and neural-tube closure (Kibar et al., 2007; Renolds et al., 2010); Identified in an individual with caudal regression with lipomyeloschisis, anorectal malformation, hydromyelia, and a tethered spinal cord. The V239I variant was also present in her unaffected mother and mildly affected brother who had dermal sinus (Kibar et al., 2007); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25208524, 17409324, 31589614, 20043994) -
Caudal regression sequence Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at