chr22-44131618-A-G

Variant names:

• chr22-44131618-A-G
• rs966460174
• NM_013327.5:c.508A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_013327.5(PARVB):​c.508A>G​(p.Ser170Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,446 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S170N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PARVB NM_013327.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.04
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARVB	NM_013327.5	c.508A>G	p.Ser170Gly	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.508A>G	p.Ser170Gly	missense_variant	Exon 5 of 13	1	NM_013327.5	ENSP00000342492.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459352 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725968

African (AFR) AF: 0.0000300 AC: 1 AN: 33372

American (AMR) AF: 0.00 AC: 0 AN: 44070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 85980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111114

Other (OTH) AF: 0.00 AC: 0 AN: 60244

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74280

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.607A>G (p.S203G) alteration is located in exon 6 (coding exon 6) of the PARVB gene. This alteration results from a A to G substitution at nucleotide position 607, causing the serine (S) at amino acid position 203 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	Benign	0.077
BayesDel_addAF	Benign	0.0021	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	.;D;T;.;.
Eigen	Benign	0.072
Eigen_PC	Benign	0.098
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T;T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.44	T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.6	.;M;.;.;.
PhyloP100		9.0
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.6	D;D;.;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0050	D;D;.;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;.
Polyphen		0.52	P;B;.;.;.
Vest4		0.39
MutPred		0.54		.;Loss of stability (P = 0.0251);.;.;.;
MVP		0.67
MPC		0.34
ClinPred		0.96	D
GERP RS		4.1
Varity_R		0.15
gMVP		0.28
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs966460174; hg19: chr22-44527498;