1-160424079-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_020335.3(VANGL2):c.1101C>A(p.Phe367Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VANGL2 NM_020335.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

Genes affected

VANGL2 (HGNC:15511): (VANGL planar cell polarity protein 2) The protein encoded by this gene is a membrane protein involved in the regulation of planar cell polarity, especially in the stereociliary bundles of the cochlea. The encoded protein transmits directional signals to individual cells or groups of cells in epithelial sheets. This protein is also involved in the development of the neural plate. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VANGL2	NM_020335.3	c.1101C>A	p.Phe367Leu	missense_variant	7/8	ENST00000368061.3
VANGL2	XM_005245357.2	c.1101C>A	p.Phe367Leu	missense_variant	8/9
VANGL2	XM_011509804.2	c.1101C>A	p.Phe367Leu	missense_variant	7/8
VANGL2	XM_047426020.1	c.1101C>A	p.Phe367Leu	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VANGL2	ENST00000368061.3	c.1101C>A	p.Phe367Leu	missense_variant	7/8	2	NM_020335.3	P1
VANGL2	ENST00000696602.1	c.1245C>A	p.Phe415Leu	missense_variant	7/8
VANGL2	ENST00000483408.1	n.281C>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.1101C>A (p.F367L) alteration is located in exon 7 (coding exon 6) of the VANGL2 gene. This alteration results from a C to A substitution at nucleotide position 1101, causing the phenylalanine (F) at amino acid position 367 to be replaced by a leucine (L). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
Eigen	Benign	-0.026
Eigen_PC	Benign	0.0037
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.082	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.24	B
Vest4		0.98
MutPred		0.75		Loss of catalytic residue at F367 (P = 0.0463);
MVP		0.80
MPC		0.90
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.88
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: chr1-160393869;