rs761812034

chr10-68210427-G-Achr10-68210427-G-Cchr10-68210427-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_032578.4(MYPN):c.3935G>A(p.Arg1312Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. R1312W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.92

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]

LOC124902443 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055026025).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000112 (17/152124) while in subpopulation AMR AF= 0.000393 (6/15272). AF 95% confidence interval is 0.00017. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4	c.3935G>A	p.Arg1312Gln	missense_variant	20/20	ENST00000358913.10
LOC124902443	XR_007062176.1	n.127+4861C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10	c.3935G>A	p.Arg1312Gln	missense_variant	20/20	1	NM_032578.4	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251416 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135874

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74300

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jun 16, 2017

- -

Dilated cardiomyopathy 1KK Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1312 of the MYPN protein (p.Arg1312Gln). This variant is present in population databases (rs761812034, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with MYPN-related conditions. ClinVar contains an entry for this variant (Variation ID: 264277). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.3935G>A (p.R1312Q) alteration is located in exon 20 (coding exon 19) of the MYPN gene. This alteration results from a G to A substitution at nucleotide position 3935, causing the arginine (R) at amino acid position 1312 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	18
Dann	Benign	0.63
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.84	T;T;.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.055	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N;.;N;.
MutationTaster	Benign	0.63	N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.44	N;N;N;.
REVEL	Benign	0.081
Sift	Benign	0.48	T;T;T;.
Sift4G	Benign	0.64	T;T;T;T
Polyphen		0.014	B;B;B;.
Vest4		0.13
MVP		0.63
MPC		0.16
ClinPred		0.11	T
GERP RS		3.8
Varity_R		0.062
gMVP		0.10

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: rs761812034; hg19: chr10-69970184; COSMIC: COSV62733162;