1-115663802-G-C

Position:

• chr1-115663802-G-C

Variant summary

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

The ENST00000355485.7(VANGL1):​c.346G>C​(p.Ala116Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A116T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VANGL1 ENST00000355485.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.94

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 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, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VANGL1	NM_138959.3	c.346G>C	p.Ala116Pro	missense_variant	4/8	ENST00000355485.7	NP_620409.1
VANGL1	NM_001172412.2	c.346G>C	p.Ala116Pro	missense_variant	4/8		NP_001165883.1
VANGL1	NM_001172411.2	c.340G>C	p.Ala114Pro	missense_variant	4/8		NP_001165882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VANGL1	ENST00000355485.7	c.346G>C	p.Ala116Pro	missense_variant	4/8	1	NM_138959.3	ENSP00000347672	P3
VANGL1	ENST00000310260.7	c.346G>C	p.Ala116Pro	missense_variant	4/8	1		ENSP00000310800	P3
VANGL1	ENST00000369509.1	c.346G>C	p.Ala116Pro	missense_variant	3/7	1		ENSP00000358522	P3
VANGL1	ENST00000369510.8	c.340G>C	p.Ala114Pro	missense_variant	4/8	1		ENSP00000358523	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.71	T;T;.;.
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.0	M;.;M;M
MutationTaster	Benign	0.59	P;P;P;P
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Uncertain	0.53
Sift	Benign	0.058	T;T;T;T
Sift4G	Uncertain	0.051	T;T;T;T
Polyphen		0.0040	B;B;B;B
Vest4		0.83
MutPred		0.71		Loss of helix (P = 0.0068);.;Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);
MVP		0.99
MPC		0.15
ClinPred		0.78	D
GERP RS		3.9
Varity_R		0.46
gMVP		0.90

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

LitVar

Other links and lift over

dbSNP: rs4839469; hg19: chr1-116206423;