5-150672499-A-G

Variant names:

• chr5-150672499-A-G
• NM_001122853.3:c.584A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001122853.3(MYOZ3):​c.584A>G​(p.Asn195Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000709 in 1,410,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MYOZ3 NM_001122853.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.79

Genes affected

MYOZ3 (HGNC:18565): (myozenin 3) The protein encoded by this gene is specifically 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]

MYOZ3-AS1 (HGNC:40846): (MYOZ3 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOZ3	NM_001122853.3	c.584A>G	p.Asn195Ser	missense_variant	Exon 6 of 7	ENST00000517768.6	NP_001116325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOZ3	ENST00000517768.6	c.584A>G	p.Asn195Ser	missense_variant	Exon 6 of 7	1	NM_001122853.3	ENSP00000428815.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410270 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 695626

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.584A>G (p.N195S) alteration is located in exon 6 (coding exon 5) of the MYOZ3 gene. This alteration results from a A to G substitution at nucleotide position 584, causing the asparagine (N) at amino acid position 195 to be replaced by a serine (S). 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	0.20
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	.;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	3.6	H;H;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.4	D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0080	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.87
MutPred		0.79		Gain of glycosylation at N195 (P = 0.017);Gain of glycosylation at N195 (P = 0.017);.;
MVP		0.95
MPC		0.82
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.41
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-150052061;