rs7079481

Variant names:

• chr10-68199485-C-A
• rs7079481
• NM_032578.4:c.3403C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-68199485-C-A
• chr10-68199485-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032578.4(MYPN):​c.3403C>A​(p.Pro1135Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,613,704 control chromosomes in the GnomAD database, including 179,304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1135P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.41 (13473 hom., cov: 31)
  • Exomes 𝑓: 0.47 (165831 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 7.91
• Publications: 47 publications found

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]

MYPN Gene-Disease associations (from GenCC):

• MYPN-related myopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• cap myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy 1KK

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006650597).
• BP6: Variant 10-68199485-C-A is Benign according to our data. Variant chr10-68199485-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032578.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYPN	NM_032578.4	MANE Select	c.3403C>A	p.Pro1135Thr	missense	Exon 17 of 20	NP_115967.2	Q86TC9-1
	MYPN	NM_001256267.2		c.3403C>A	p.Pro1135Thr	missense	Exon 18 of 21	NP_001243196.1	Q86TC9-1
	MYPN	NM_001256268.2		c.2521C>A	p.Pro841Thr	missense	Exon 21 of 24	NP_001243197.1	A0A087WX60

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYPN	ENST00000358913.10	TSL:1 MANE Select	c.3403C>A	p.Pro1135Thr	missense	Exon 17 of 20	ENSP00000351790.5	Q86TC9-1
	MYPN	ENST00000540630.6	TSL:1	c.3457C>A	p.Pro1153Thr	missense	Exon 17 of 20	ENSP00000441668.3	A0A8J9ASZ5
	MYPN	ENST00000613327.5	TSL:1	c.3403C>A	p.Pro1135Thr	missense	Exon 18 of 21	ENSP00000480757.2	Q86TC9-1

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61673 AN: 151844 Hom.: 13474 Cov.: 31

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.417

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.392

GnomAD2 exomes AF: 0.432 AC: 108580 AN: 251350 AF XY: 0.437

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.419

Gnomad ASJ exome AF: 0.333

Gnomad EAS exome AF: 0.218

Gnomad FIN exome AF: 0.527

Gnomad NFE exome AF: 0.487

Gnomad OTH exome AF: 0.426

GnomAD4 exome AF: 0.472 AC: 689882 AN: 1461740 Hom.: 165831 Cov.: 55 AF XY: 0.472 AC XY: 343063 AN XY: 727180

African (AFR) AF: 0.255 AC: 8532 AN: 33478

American (AMR) AF: 0.416 AC: 18583 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 8627 AN: 26136

East Asian (EAS) AF: 0.266 AC: 10547 AN: 39694

South Asian (SAS) AF: 0.435 AC: 37491 AN: 86252

European-Finnish (FIN) AF: 0.524 AC: 27966 AN: 53414

Middle Eastern (MID) AF: 0.346 AC: 1997 AN: 5768

European-Non Finnish (NFE) AF: 0.494 AC: 549819 AN: 1111888

Other (OTH) AF: 0.436 AC: 26320 AN: 60388

GnomAD4 genome AF: 0.406 AC: 61683 AN: 151964 Hom.: 13473 Cov.: 31 AF XY: 0.406 AC XY: 30164 AN XY: 74268

African (AFR) AF: 0.261 AC: 10810 AN: 41428

American (AMR) AF: 0.416 AC: 6361 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1127 AN: 3468

East Asian (EAS) AF: 0.236 AC: 1217 AN: 5164

South Asian (SAS) AF: 0.429 AC: 2063 AN: 4808

European-Finnish (FIN) AF: 0.527 AC: 5562 AN: 10556

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.490 AC: 33267 AN: 67954

Other (OTH) AF: 0.392 AC: 823 AN: 2100

Alfa AF: 0.451 Hom.: 78630

Bravo AF: 0.386

TwinsUK AF: 0.496 AC: 1839

ALSPAC AF: 0.485 AC: 1869

ESP6500AA AF: 0.264 AC: 1163

ESP6500EA AF: 0.479 AC: 4116

ExAC AF: 0.432 AC: 52489

Asia WGS AF: 0.306 AC: 1064 AN: 3478

EpiCase AF: 0.479

EpiControl AF: 0.469

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Dilated cardiomyopathy 1KK (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	MYPN-related myopathy (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.97	L
PhyloP100		7.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.56
MPC		0.65
ClinPred		0.017	T
GERP RS		5.4
Varity_R		0.52
gMVP		0.48
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7079481; hg19: chr10-69959242; COSMIC: COSV62741889;