rs145701607

Variant names:

• chr10-68148356-C-T
• rs145701607
• NM_032578.4:c.1134C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_032578.4(MYPN):​c.1134C>T​(p.Ile378Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00691 in 1,611,158 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (39 hom.)
• Consequence: MYPN NM_032578.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.70

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]

LOC107984240 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 10-68148356-C-T is Benign according to our data. Variant chr10-68148356-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 138415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68148356-C-T is described in Lovd as [Benign]. Variant chr10-68148356-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.7 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00524 (798/152244) while in subpopulation SAS AF= 0.00872 (42/4816). AF 95% confidence interval is 0.0075. There are 3 homozygotes in gnomad4. There are 396 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 798 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYPN	NM_032578.4	c.1134C>T	p.Ile378Ile	synonymous_variant	Exon 5 of 20	ENST00000358913.10	NP_115967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYPN	ENST00000358913.10	c.1134C>T	p.Ile378Ile	synonymous_variant	Exon 5 of 20	1	NM_032578.4	ENSP00000351790.5

Frequencies

GnomAD3 genomes AF: 0.00524 AC: 797 AN: 152126 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00649

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00871

Gnomad FIN AF: 0.00208

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00806

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00613 AC: 1541 AN: 251364 Hom.: 10 AF XY: 0.00673 AC XY: 915 AN XY: 135862

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00445

Gnomad ASJ exome AF: 0.00844

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00967

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00782

Gnomad OTH exome AF: 0.00977

GnomAD4 exome AF: 0.00709 AC: 10342 AN: 1458914 Hom.: 39 Cov.: 30 AF XY: 0.00736 AC XY: 5343 AN XY: 726034

Gnomad4 AFR exome AF: 0.00141

Gnomad4 AMR exome AF: 0.00463

Gnomad4 ASJ exome AF: 0.00777

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00955

Gnomad4 FIN exome AF: 0.00178

Gnomad4 NFE exome AF: 0.00760

Gnomad4 OTH exome AF: 0.00753

GnomAD4 genome AF: 0.00524 AC: 798 AN: 152244 Hom.: 3 Cov.: 32 AF XY: 0.00532 AC XY: 396 AN XY: 74428

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.00648

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00872

Gnomad4 FIN AF: 0.00208

Gnomad4 NFE AF: 0.00806

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00721 Hom.: 1

Bravo AF: 0.00548

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00960

EpiControl AF: 0.00883

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Mar 10, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 24, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ile378Ile in exon 6 of MYPN: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 0.9% (75/8600) of Eur opean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs145701607). -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1KK Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 10, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Aug 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYPN: BP4, BS2 -

Cardiovascular phenotype Benign:1

Jul 31, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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
BayesDel_noAF	Benign	-0.23
CADD	Benign	7.9
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs145701607; hg19: chr10-69908113; COSMIC: COSV62738221;