rs71578935

Variant names:

• chr5-137875917-G-A
• rs71578935
• NM_006790.3:c.445G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-137875917-G-A
• chr5-137875917-G-C
• chr5-137875917-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006790.3(MYOT):​c.445G>A​(p.Glu149Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E149Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYOT NM_006790.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.11
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.269399).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOT	NM_006790.3	c.445G>A	p.Glu149Lys	missense_variant	Exon 3 of 10	ENST00000239926.9	NP_006781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOT	ENST00000239926.9	c.445G>A	p.Glu149Lys	missense_variant	Exon 3 of 10	1	NM_006790.3	ENSP00000239926.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461776 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Pathogenic	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.47	T
PhyloP100		8.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.031	D;D
Vest4		0.36
MutPred		0.37		Gain of ubiquitination at E149 (P = 0.0128);.;
MVP		0.92
MPC		0.63
ClinPred		0.98	D
GERP RS		5.7
gMVP		0.30
Mutation Taster		=278/22	polymorphism

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: rs71578935; hg19: chr5-137211606; COSMIC: COSV53514485; COSMIC: COSV53514485;