chr2-218425705-T-C

Position:

• chr2-218425705-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_007127.3(VIL1):​c.241T>C​(p.Tyr81His) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VIL1 NM_007127.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.90

Genes affected

VIL1 (HGNC:12690): (villin 1) This gene encodes a member of a family of calcium-regulated actin-binding proteins. This protein represents a dominant part of the brush border cytoskeleton which functions in the capping, severing, and bundling of actin filaments. Two mRNAs of 2.7 kb and 3.5 kb have been observed; they result from utilization of alternate poly-adenylation signals present in the terminal exon. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a mutagenesis_site Reduces activities regarding actin nucleating and actin severing, lamellipodium or ruffle localization and cell migration. Complete loss of phosphorylation and interaction with PLCG1, does not reduce lamellipodium or ruffle localization, inhibits cell migration; when associated with F-46; F-60; F-256; F-286; F-324; F-461; F-555; F-604 and F-725. Inhibits lamellipodia localization but does not reduce interaction with PLCG1; when associated with F-46; F-60 and F-256. (size 0) in uniprot entity VILI_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VIL1	NM_007127.3	c.241T>C	p.Tyr81His	missense_variant	4/20	ENST00000248444.10	NP_009058.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VIL1	ENST00000248444.10	c.241T>C	p.Tyr81His	missense_variant	4/20	1	NM_007127.3	ENSP00000248444	P1
VIL1	ENST00000440053.1	c.241T>C	p.Tyr81His	missense_variant	3/9	1		ENSP00000409270
VIL1	ENST00000454069.5	c.241T>C	p.Tyr81His	missense_variant	4/6	3		ENSP00000412657
VIL1	ENST00000392114.6	c.-183-3763T>C		intron_variant		2		ENSP00000375962

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

VIL1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2024

The VIL1 c.241T>C variant is predicted to result in the amino acid substitution p.Tyr81His. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D;T;D
Sift4G	Uncertain	0.024	D;T;T
Polyphen		1.0	D;.;.
Vest4		0.80
MutPred		0.65		Gain of disorder (P = 0.0294);Gain of disorder (P = 0.0294);Gain of disorder (P = 0.0294);
MVP		0.55
MPC		0.85
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.70

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: chr2-219290428;