NM_006790.3:c.164C>T

Variant names:

• chr5-137870815-C-T
• rs121908457
• NM_006790.3:c.164C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PM1 PM2 PP5_Very_Strong BP4

The NM_006790.3(MYOT):​c.164C>T​(p.Ser55Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOT NM_006790.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.43
• Publications: 22 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 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_006790.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-137870815-C-T is Pathogenic according to our data. Variant chr5-137870815-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.40440857). . 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOT	NM_006790.3	MANE Select	c.164C>T	p.Ser55Phe	missense	Exon 2 of 10	NP_006781.1
	MYOT	NM_001300911.2		c.-120-62C>T		intron	N/A	NP_001287840.1
	MYOT	NM_001135940.2		c.-197+290C>T		intron	N/A	NP_001129412.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOT	ENST00000239926.9	TSL:1 MANE Select	c.164C>T	p.Ser55Phe	missense	Exon 2 of 10	ENSP00000239926.4
	MYOT	ENST00000515645.1	TSL:2	c.-120-62C>T		intron	N/A	ENSP00000426281.1
	MYOT	ENST00000421631.6	TSL:2	c.-197+290C>T		intron	N/A	ENSP00000391185.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Myofibrillar myopathy 3 (3)
2	-	-	not provided (2)
1	-	-	Lower limb pain;C1836450:Distal lower limb muscle weakness;C1843663:Urinary bladder sphincter dysfunction;C1848736:Distal amyotrophy;C1866141:Foot dorsiflexor weakness;C4021082:Fatty replacement of skeletal muscle;C4021726:EMG: myopathic abnormalities;C4022159:Muscle fiber inclusion bodies (1)
1	-	-	Progressive proximal muscle weakness;C1836609:Progressive distal muscle weakness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.35	T
PhyloP100		5.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.18	T
Vest4		0.49
MutPred		0.24		Loss of phosphorylation at S55 (P = 0.0523)
MVP		0.92
MPC		0.43
ClinPred		0.95	D
GERP RS		6.0
gMVP		0.62
Mutation Taster		=15/85	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: rs121908457; hg19: chr5-137206504; COSMIC: COSV53514808;