22-44131613-G-A

Variant names:

• chr22-44131613-G-A
• rs550575928
• NM_013327.5:c.503G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_013327.5(PARVB):​c.503G>A​(p.Arg168Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R168W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PARVB NM_013327.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.10
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18455425).
• BP6: Variant 22-44131613-G-A is Benign according to our data. Variant chr22-44131613-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3928144.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARVB	NM_013327.5	c.503G>A	p.Arg168Gln	missense_variant	Exon 5 of 13	ENST00000338758.12	NP_037459.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARVB	ENST00000338758.12	c.503G>A	p.Arg168Gln	missense_variant	Exon 5 of 13	1	NM_013327.5	ENSP00000342492.6

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249732 AF XY: 0.0000148

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461052 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726810

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.0000224 AC: 1 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.000356 AC: 2 AN: 5612

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111698

Other (OTH) AF: 0.0000166 AC: 1 AN: 60346

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74478

African (AFR) AF: 0.0000721 AC: 3 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 13, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;D;T;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;L;.;.;.
PhyloP100		2.1
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.1	N;N;.;N;N
REVEL	Benign	0.028
Sift	Benign	0.056	T;T;.;D;T
Sift4G	Benign	0.14	T;T;T;T;.
Polyphen		0.15	B;B;.;.;.
Vest4		0.17
MutPred		0.56		.;Loss of MoRF binding (P = 0.0127);.;.;.;
MVP		0.61
MPC		0.19
ClinPred		0.20	T
GERP RS		1.2
Varity_R		0.035
gMVP		0.12
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs550575928; hg19: chr22-44527493; COSMIC: COSV107441726; COSMIC: COSV107441726;