11-12504399-C-A

Variant names:

• chr11-12504399-C-A
• rs781246322
• NM_018222.5:c.627C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018222.5(PARVA):​c.627C>A​(p.Asp209Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,460,740 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: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: PARVA NM_018222.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.353

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045698762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARVA	NM_018222.5	c.627C>A	p.Asp209Glu	missense_variant	Exon 6 of 13	ENST00000334956.15	NP_060692.3
PARVA	XM_005253015.4	c.495C>A	p.Asp165Glu	missense_variant	Exon 6 of 13		XP_005253072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARVA	ENST00000334956.15	c.627C>A	p.Asp209Glu	missense_variant	Exon 6 of 13	1	NM_018222.5	ENSP00000334008.9
PARVA	ENST00000528916.1	c.519C>A	p.Asp173Glu	missense_variant	Exon 6 of 8	5		ENSP00000435860.1
PARVA	ENST00000533345.5	n.604C>A		non_coding_transcript_exon_variant	Exon 6 of 8	5
PARVA	ENST00000533392.1	n.*44C>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1460740 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12 AN XY: 726694

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000243

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.747C>A (p.D249E) alteration is located in exon 6 (coding exon 6) of the PARVA gene. This alteration results from a C to A substitution at nucleotide position 747, causing the aspartic acid (D) at amino acid position 249 to be replaced by a glutamic acid (E). 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	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.67
DEOGEN2	Benign	0.091	T;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.86	D;.;D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.046	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.3	N;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	1.4	.;.;N
REVEL	Benign	0.14
Sift	Benign	1.0	.;.;T
Sift4G	Benign	1.0	.;.;T
Polyphen		0.0	B;.;.
MutPred		0.26		Gain of MoRF binding (P = 0.2601);.;.;
MVP		0.11
MPC		0.32
ClinPred		0.30	T
GERP RS		3.1
Varity_R		0.095
gMVP		0.22

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: rs781246322; hg19: chr11-12525946;