rs147596628

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_032578.4(MYPN):​c.1130G>A​(p.Arg377Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000894 in 1,611,770 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00093 ( 3 hom. )

Consequence

MYPN
NM_032578.4 missense, splice_region

Scores

3
16
Splicing: ADA: 1.000
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6

Conservation

PhyloP100: 4.34
Variant links:
Genes affected
MYPN (HGNC:23246): (myopalladin) Striated muscle in vertebrates comprises large proteins which must be organized properly to contract efficiently. Z-lines in striated muscle are a sign of this organization, representing the ends of actin thin filaments, titin, nebulin or nebulette and accessory proteins required for structure and function. This gene encodes a protein which interacts with nebulin in skeletal muscle or nebulette in cardiac muscle and alpha-actinin. In addition, this gene product can interact with a protein with the I-band indicating it has a regulatory as well as structural function. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6
Variant 10-68145526-G-A is Benign according to our data. Variant chr10-68145526-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191749.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=4}. Variant chr10-68145526-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000546 (83/152106) while in subpopulation NFE AF= 0.000897 (61/67988). AF 95% confidence interval is 0.000716. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 83 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYPNNM_032578.4 linkuse as main transcriptc.1130G>A p.Arg377Gln missense_variant, splice_region_variant 4/20 ENST00000358913.10 NP_115967.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYPNENST00000358913.10 linkuse as main transcriptc.1130G>A p.Arg377Gln missense_variant, splice_region_variant 4/201 NM_032578.4 ENSP00000351790.5 Q86TC9-1

Frequencies

GnomAD3 genomes
AF:
0.000546
AC:
83
AN:
151990
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000655
Gnomad ASJ
AF:
0.000289
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000897
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000534
AC:
134
AN:
251008
Hom.:
0
AF XY:
0.000464
AC XY:
63
AN XY:
135660
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000867
Gnomad ASJ exome
AF:
0.000596
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.0000931
Gnomad NFE exome
AF:
0.000705
Gnomad OTH exome
AF:
0.000980
GnomAD4 exome
AF:
0.000930
AC:
1358
AN:
1459664
Hom.:
3
Cov.:
29
AF XY:
0.000916
AC XY:
665
AN XY:
726302
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.000895
Gnomad4 ASJ exome
AF:
0.000421
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000244
Gnomad4 FIN exome
AF:
0.000132
Gnomad4 NFE exome
AF:
0.00112
Gnomad4 OTH exome
AF:
0.000498
GnomAD4 genome
AF:
0.000546
AC:
83
AN:
152106
Hom.:
0
Cov.:
32
AF XY:
0.000417
AC XY:
31
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.000241
Gnomad4 AMR
AF:
0.000654
Gnomad4 ASJ
AF:
0.000289
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000897
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000819
Hom.:
1
Bravo
AF:
0.000544
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.00182
AC:
7
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.000930
AC:
8
ExAC
AF:
0.000486
AC:
59
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000709
EpiControl
AF:
0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicApr 30, 2021- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 12, 2021In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 191749; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23861362, 28050010) -
Uncertain significance, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2023MYPN: BP4 -
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 09, 2015The p.Arg377Gln variant in MYPN has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.1% (13/11570) of Latino chromo somes and 43/66674 European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs147596628). Computational prediction tools and conservation analysis suggest that this variant may not impact the pro tein, though this information is not predictive enough to rule out pathogenicity . This variant is located in the last base of the exon, which is part of the 5' splice region. Computational tools do suggest an impact to splicing; however, th is information is not predictive enough to determine pathogenicity. In summary, in the presence of conflicting data, the clinical significance of the p.Arg377Gl n variant is uncertain. -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 05, 2024Variant summary: MYPN c.1130G>A (p.Arg377Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 251008 control chromosomes (gnomAD). The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYPN causing Cardiomyopathy phenotype (5e-05), strongly suggesting that the variant is benign. c.1130G>A has been reported in the literature in at-least one pediatric DCM proband without strong evidence for causality (example: Khan-2022). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34935411). ClinVar contains an entry for this variant (Variation ID: 191749). Based on the evidence outlined above, the variant was classified as likely benign. -
Dilated cardiomyopathy 1KK Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtDec 11, 2015- -
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingCenter for Advanced Laboratory Medicine, UC San Diego Health, University of California San DiegoJan 10, 2019- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 05, 2019This 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
0.10
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.22
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Benign
0.023
.;.;.;T;.
Eigen
Benign
0.16
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Benign
0.67
D
LIST_S2
Uncertain
0.87
D;D;.;D;D
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.035
T;T;T;T;T
MetaSVM
Benign
-0.67
T
MutationAssessor
Benign
0.98
L;.;L;.;L
PrimateAI
Benign
0.44
T
PROVEAN
Benign
0.46
N;N;N;.;N
REVEL
Benign
0.12
Sift
Benign
0.48
T;T;T;.;T
Sift4G
Benign
0.76
T;T;T;T;T
Polyphen
0.026
B;B;B;.;D
Vest4
0.42
MVP
0.68
MPC
0.16
ClinPred
0.018
T
GERP RS
5.2
Varity_R
0.062
gMVP
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.99
SpliceAI score (max)
0.39
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.39
Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs147596628; hg19: chr10-69905283; API