10-73633916-A-C

Position:

• chr10-73633916-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP3 BP4 BP6

The NM_021245.4(MYOZ1):​c.652T>G​(p.Tyr218Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000773 in 1,610,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (0 hom.)
• Consequence: MYOZ1 NM_021245.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:3
• Conservation: PhyloP100: 8.66

Genes affected

MYOZ1 (HGNC:13752): (myozenin 1) The protein encoded by this gene is primarily expressed in the skeletal muscle, and belongs to the myozenin family. Members of this family function as calcineurin-interacting proteins that help tether calcineurin to the sarcomere of cardiac and skeletal muscle. They play an important role in modulation of calcineurin signaling. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.30444843).
• BP6: Variant 10-73633916-A-C is Benign according to our data. Variant chr10-73633916-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 1174829.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-73633916-A-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOZ1	NM_021245.4	c.652T>G	p.Tyr218Asp	missense_variant	5/6	ENST00000359322.5	NP_067068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOZ1	ENST00000359322.5	c.652T>G	p.Tyr218Asp	missense_variant	5/6	1	NM_021245.4	ENSP00000352272.4

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000876 AC: 218 AN: 248992 Hom.: 0 AF XY: 0.000928 AC XY: 125 AN XY: 134684

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000766 AC: 1117 AN: 1458576 Hom.: 0 Cov.: 31 AF XY: 0.000793 AC XY: 575 AN XY: 725422

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00206

Gnomad4 NFE exome AF: 0.000870

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.000840 AC: 128 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000953 AC XY: 71 AN XY: 74472

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000631

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000766 AC: 93

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.000891

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: no assertion criteria provided

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.3	M
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-8.8	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.98
MPC		0.35
ClinPred		0.29	T
GERP RS		6.2
Varity_R		0.84
gMVP		0.87

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: rs145071008; hg19: chr10-75393674;