11-12477896-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018222.5(PARVA):c.347T>C(p.Val116Ala) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PARVA NM_018222.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

Genes affected

PARVA (HGNC:14652): (parvin alpha) This gene encodes a member of the parvin family of actin-binding proteins. Parvins are associated with focal contacts and contain calponin homology domains that bind to actin filaments. The encoded protein is part of the integrin-linked kinase signaling complex and plays a role in cell adhesion, motility and survival. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PARVA	NM_018222.5	c.347T>C	p.Val116Ala	missense_variant	4/13	ENST00000334956.15
PARVA	XM_005253015.4	c.215T>C	p.Val72Ala	missense_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PARVA	ENST00000334956.15	c.347T>C	p.Val116Ala	missense_variant	4/13	1	NM_018222.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jan 02, 2024

The c.467T>C (p.V156A) alteration is located in exon 4 (coding exon 4) of the PARVA gene. This alteration results from a T to C substitution at nucleotide position 467, causing the valine (V) at amino acid position 156 to be replaced by an alanine (A). 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	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
REVEL	Pathogenic	0.97
Polyphen		1.0	D;.;.
MutPred		0.79		Loss of methylation at K117 (P = 0.0455);.;.;
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.64
gMVP		0.72

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: rs763435438; hg19: chr11-12499443;