chr5-137870821-C-T

Variant names:

• chr5-137870821-C-T
• rs28937597
• NM_006790.3:c.170C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PS3 PM1 PM2 PP5_Very_Strong BP4

The NM_006790.3(MYOT):​c.170C>T​(p.Thr57Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000515894: A mouse model carrying the equivalent variant in murine MYOT had progressive myofibrillar pathology including Z-disc streaming, excess myofibrillar vacuolization, and plaque-like myofibrillar aggregation (Garvey et al., 2006)" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOT NM_006790.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 2.77
• Publications: 19 publications found

Genes affected

MYOT (HGNC:12399): (myotilin) This gene encodes a cystoskeletal protein which plays a significant role in the stability of thin filaments during muscle contraction. This protein binds F-actin, crosslinks actin filaments, and prevents latrunculin A-induced filament disassembly. Mutations in this gene have been associated with limb-girdle muscular dystrophy and myofibrillar myopathies. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.[provided by RefSeq, Oct 2008]

PKD2L2-DT (HGNC:55557): (PKD2L2 divergent transcript)

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000515894: A mouse model carrying the equivalent variant in murine MYOT had progressive myofibrillar pathology including Z-disc streaming, excess myofibrillar vacuolization, and plaque-like myofibrillar aggregation (Garvey et al., 2006); SCV000842842: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 16801328, 21361873); SCV000761562: Experimental studies have shown that this missense change affects MYOT function (PMID: 16801328).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_006790.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-137870821-C-T is Pathogenic according to our data. Variant chr5-137870821-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20068157). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006790.3. 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
	MYOT	NM_006790.3	MANE Select	c.170C>T	p.Thr57Ile	missense	Exon 2 of 10	NP_006781.1	A0A0C4DFM5
	MYOT	NM_001300911.2		c.-120-56C>T		intron	N/A	NP_001287840.1	B4DT68
	MYOT	NM_001135940.2		c.-197+296C>T		intron	N/A	NP_001129412.1	Q9UBF9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOT	ENST00000239926.9	TSL:1 MANE Select	c.170C>T	p.Thr57Ile	missense	Exon 2 of 10	ENSP00000239926.4	A0A0C4DFM5
	MYOT	ENST00000968642.1		c.170C>T	p.Thr57Ile	missense	Exon 2 of 10	ENSP00000638701.1
	MYOT	ENST00000968644.1		c.170C>T	p.Thr57Ile	missense	Exon 1 of 8	ENSP00000638703.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000258 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Myofibrillar myopathy 3 (4)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.040
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.84	T
PhyloP100		2.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.23
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.29	T
Vest4		0.24
MutPred		0.15		Loss of glycosylation at T57 (P = 0.0406)
MVP		0.81
MPC		0.29
ClinPred		0.61	D
GERP RS		6.0
gMVP		0.55
Mutation Taster		=25/75	disease causing (ClinVar)

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: rs28937597; hg19: chr5-137206510;