rs527628617

chr10-68145477-G-Achr10-68145477-G-Cchr10-68145477-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032578.4(MYPN):c.1081G>A(p.Val361Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 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. V361F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYPN NM_032578.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19858974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4	c.1081G>A	p.Val361Ile	missense_variant, splice_region_variant	4/20	ENST00000358913.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10	c.1081G>A	p.Val361Ile	missense_variant, splice_region_variant	4/20	1	NM_032578.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1KK Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 29, 2020

This sequence change replaces valine with isoleucine at codon 361 of the MYPN protein (p.Val361Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MYPN-related disease. ClinVar contains an entry for this variant (Variation ID: 544038). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.083
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.70	T;T;.;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;L;.;L
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.57	N;N;N;.;N
REVEL	Benign	0.060
Sift	Benign	0.091	T;T;T;.;T
Sift4G	Benign	0.087	T;T;T;T;T
Polyphen		0.0010	B;B;B;.;B
Vest4		0.20
MutPred		0.20		Loss of catalytic residue at V361 (P = 0.0571);.;Loss of catalytic residue at V361 (P = 0.0571);.;Loss of catalytic residue at V361 (P = 0.0571);
MVP		0.68
MPC		0.11
ClinPred		0.67	D
GERP RS		5.2
Varity_R		0.060
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs527628617; hg19: chr10-69905234;