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GeneBe

rs1554852297

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032578.4(MYPN):​c.3877G>A​(p.Asp1293Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D1293D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

MYPN
NM_032578.4 missense

Scores

5
7
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.76
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYPNNM_032578.4 linkuse as main transcriptc.3877G>A p.Asp1293Asn missense_variant 20/20 ENST00000358913.10
LOC124902443XR_007062176.1 linkuse as main transcriptn.127+4919C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYPNENST00000358913.10 linkuse as main transcriptc.3877G>A p.Asp1293Asn missense_variant 20/201 NM_032578.4 P1Q86TC9-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Dilated cardiomyopathy 1KK Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 30, 2017In summary, this variant has uncertain impact on MYPN function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with a MYPN-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 1293 of the MYPN protein (p.Asp1293Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.49
BayesDel_addAF
Benign
-0.067
T
BayesDel_noAF
Benign
-0.33
CADD
Pathogenic
26
DANN
Pathogenic
1.0
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;.;D
M_CAP
Benign
0.034
D
MetaRNN
Uncertain
0.52
D;D;D;D
MetaSVM
Benign
-0.50
T
MutationAssessor
Uncertain
2.1
M;.;M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Uncertain
-3.3
D;D;D;.
REVEL
Uncertain
0.29
Sift
Benign
0.049
D;D;D;.
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;D;D;.
Vest4
0.53
MutPred
0.29
Gain of MoRF binding (P = 0.0417);.;Gain of MoRF binding (P = 0.0417);.;
MVP
0.87
MPC
0.57
ClinPred
0.99
D
GERP RS
6.2
Varity_R
0.36
gMVP
0.59

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

LitVar

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

Other links and lift over

dbSNP: rs1554852297; hg19: chr10-69970126; API