22-44131534-G-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_013327.5(PARVB):​c.424G>A​(p.Glu142Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

PARVB
NM_013327.5 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.87

Publications

6 publications found
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4
Computational evidence support a benign effect (MetaRNN=0.24427947).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PARVBNM_013327.5 linkc.424G>A p.Glu142Lys missense_variant Exon 5 of 13 ENST00000338758.12 NP_037459.2 Q9HBI1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PARVBENST00000338758.12 linkc.424G>A p.Glu142Lys missense_variant Exon 5 of 13 1 NM_013327.5 ENSP00000342492.6 Q9HBI1-1

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152126
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000119
AC:
30
AN:
251392
AF XY:
0.000110
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000237
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000120
AC:
176
AN:
1461878
Hom.:
0
Cov.:
31
AF XY:
0.000127
AC XY:
92
AN XY:
727240
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.0000447
AC:
2
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26136
East Asian (EAS)
AF:
0.0000504
AC:
2
AN:
39698
South Asian (SAS)
AF:
0.0000348
AC:
3
AN:
86256
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53420
Middle Eastern (MID)
AF:
0.000173
AC:
1
AN:
5768
European-Non Finnish (NFE)
AF:
0.000142
AC:
158
AN:
1112002
Other (OTH)
AF:
0.000116
AC:
7
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
9
19
28
38
47
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152244
Hom.:
0
Cov.:
32
AF XY:
0.000107
AC XY:
8
AN XY:
74440
show subpopulations
African (AFR)
AF:
0.0000481
AC:
2
AN:
41552
American (AMR)
AF:
0.00
AC:
0
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.000288
AC:
1
AN:
3470
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5168
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.000191
AC:
13
AN:
68012
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.511
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000321
Hom.:
1
Bravo
AF:
0.0000982
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000123
AC:
15
EpiCase
AF:
0.000218
EpiControl
AF:
0.000296

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 13, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.523G>A (p.E175K) alteration is located in exon 6 (coding exon 6) of the PARVB gene. This alteration results from a G to A substitution at nucleotide position 523, causing the glutamic acid (E) at amino acid position 175 to be replaced by a lysine (K). 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
0.68
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.20
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
.;D;T;.;.
Eigen
Benign
-0.040
Eigen_PC
Benign
-0.0065
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.96
D;D;D;D;D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.24
T;T;T;T;T
MetaSVM
Benign
-0.82
T
MutationAssessor
Pathogenic
3.0
.;M;.;.;.
PhyloP100
7.9
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-3.3
D;D;.;D;D
REVEL
Benign
0.20
Sift
Uncertain
0.027
D;D;.;D;D
Sift4G
Benign
0.11
T;T;T;T;.
Polyphen
0.31
B;B;.;.;.
Vest4
0.68
MVP
0.66
MPC
0.32
ClinPred
0.61
D
GERP RS
4.2
Varity_R
0.41
gMVP
0.42
Mutation Taster
=50/50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs183013426; hg19: chr22-44527414; COSMIC: COSV58685908; COSMIC: COSV58685908; API