3-37994376-A-C

Position:

• chr3-37994376-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015873.4(VILL):​c.251A>C​(p.Gln84Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VILL NM_015873.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.45

Genes affected

VILL (HGNC:30906): (villin like) The protein encoded by this gene belongs to the villin/gelsolin family. It contains 6 gelsolin-like repeats and a headpiece domain. It may play a role in actin-bundling. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4228066).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VILL	NM_015873.4	c.251A>C	p.Gln84Pro	missense_variant	4/20	ENST00000383759.7	NP_056957.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VILL	ENST00000383759.7	c.251A>C	p.Gln84Pro	missense_variant	4/20	5	NM_015873.4	ENSP00000373266	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460044 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726394

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The c.251A>C (p.Q84P) alteration is located in exon 3 (coding exon 3) of the VILL gene. This alteration results from a A to C substitution at nucleotide position 251, causing the glutamine (Q) at amino acid position 84 to be replaced by a proline (P). 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	0.15
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.071	T;.;T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.40	T;T;T;.
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.4	M;.;.;M
MutationTaster	Benign	0.79	D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Benign	0.083	T;T;T;T
Polyphen		0.030	B;.;.;B
Vest4		0.24
MutPred		0.68		Gain of glycosylation at Q84 (P = 0.0462);Gain of glycosylation at Q84 (P = 0.0462);Gain of glycosylation at Q84 (P = 0.0462);Gain of glycosylation at Q84 (P = 0.0462);
MVP		0.35
MPC		0.25
ClinPred		0.65	D
GERP RS		1.3
Varity_R		0.56
gMVP		0.83

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: chr3-38035867;