22-44132960-C-G

Variant names:

• chr22-44132960-C-G
• NM_013327.5:c.584C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_013327.5(PARVB):​c.584C>G​(p.Ala195Gly) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A195V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PARVB NM_013327.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.92

Genes affected

PARVB (HGNC:14653): (parvin beta) This gene encodes a member of the parvin family of actin-binding proteins, which play a role in cytoskeleton organization and cell adhesion. These proteins are associated with focal contacts and contain calponin homology domains that bind to actin filaments. This family member binds to alphaPIX and alpha-actinin, and it can inhibit the activity of integrin-linked kinase. This protein also functions in tumor suppression. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARVB	NM_013327.5	c.584C>G	p.Ala195Gly	missense_variant	Exon 6 of 13	ENST00000338758.12	NP_037459.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARVB	ENST00000338758.12	c.584C>G	p.Ala195Gly	missense_variant	Exon 6 of 13	1	NM_013327.5	ENSP00000342492.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.683C>G (p.A228G) alteration is located in exon 7 (coding exon 7) of the PARVB gene. This alteration results from a C to G substitution at nucleotide position 683, causing the alanine (A) at amino acid position 228 to be replaced by a glycine (G). 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	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	.;D;T;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.9	.;M;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.4	D;D;.;D;D
REVEL	Benign	0.28
Sift	Benign	0.071	T;T;.;D;D
Sift4G	Benign	0.17	T;T;T;D;.
Polyphen		0.97	D;P;.;.;.
Vest4		0.74
MutPred		0.77		.;Loss of stability (P = 0.0256);.;.;.;
MVP		0.67
MPC		0.59
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.56
gMVP		0.56

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: chr22-44528840;