rs10997948

chr10-68150045-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_032578.4(MYPN):c.1251G>A(p.Gln417=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0834 in 1,611,476 control chromosomes in the GnomAD database, including 6,240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (898 hom., cov: 32)
  • Exomes 𝑓: 0.082 (5342 hom.)
• Consequence: MYPN NM_032578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 2.52

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=-0.46).
• BP6: Variant 10-68150045-G-A is Benign according to our data. Variant chr10-68150045-G-A is described in ClinVar as [Benign]. Clinvar id is 31794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68150045-G-A is described in Lovd as [Benign]. Variant chr10-68150045-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4	c.1251G>A	p.Gln417=	synonymous_variant	6/20	ENST00000358913.10
LOC107984240	XR_001747479.2	n.206-3327C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10	c.1251G>A	p.Gln417=	synonymous_variant	6/20	1	NM_032578.4	P1

Frequencies

GnomAD3 genomes AF: 0.0992 AC: 15076 AN: 151998 Hom.: 894 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0740

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.0921

Gnomad FIN AF: 0.0581

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0825

Gnomad OTH AF: 0.0937

GnomAD3 exomes AF: 0.0811 AC: 20383 AN: 251326 Hom.: 1078 AF XY: 0.0831 AC XY: 11287 AN XY: 135836

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.0479

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.00745

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.0580

Gnomad NFE exome AF: 0.0858

Gnomad OTH exome AF: 0.0853

GnomAD4 exome AF: 0.0818 AC: 119348 AN: 1459360 Hom.: 5342 Cov.: 31 AF XY: 0.0830 AC XY: 60267 AN XY: 726138

Gnomad4 AFR exome AF: 0.154

Gnomad4 AMR exome AF: 0.0498

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.00345

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.0591

Gnomad4 NFE exome AF: 0.0815

Gnomad4 OTH exome AF: 0.0874

GnomAD4 genome AF: 0.0992 AC: 15090 AN: 152116 Hom.: 898 Cov.: 32 AF XY: 0.0976 AC XY: 7260 AN XY: 74372

Gnomad4 AFR AF: 0.156

Gnomad4 AMR AF: 0.0738

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.00501

Gnomad4 SAS AF: 0.0916

Gnomad4 FIN AF: 0.0581

Gnomad4 NFE AF: 0.0826

Gnomad4 OTH AF: 0.0932

Alfa AF: 0.0898 Hom.: 1086

Bravo AF: 0.103

Asia WGS AF: 0.0610 AC: 212 AN: 3478

EpiCase AF: 0.0878

EpiControl AF: 0.0865

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2014	p.Gln417Gln in exon 7 of MYPN: This variant is not expected to have clinical sig nificance because it has been identified in 16% (702/4406) of African American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/; dbSNPrs10997948). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2013	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. -

Dilated cardiomyopathy 1KK Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2015

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. -

not provided Other:1

not provided, no classification provided

curation

Leiden Muscular Dystrophy (MYPN)

Apr 27, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	9.1
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs10997948; hg19: chr10-69909802;