rs145427063

Positions:

• chr5-137887289-T-A
• chr5-137887289-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_006790.3(MYOT):​c.1401T>A​(p.Asn467Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. N467N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: MYOT NM_006790.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: -1.30

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

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17482439).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000186 (272/1461776) while in subpopulation NFE AF= 0.000222 (247/1111950). AF 95% confidence interval is 0.000199. There are 0 homozygotes in gnomad4_exome. There are 148 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOT	NM_006790.3	c.1401T>A	p.Asn467Lys	missense_variant	10/10	ENST00000239926.9	NP_006781.1
PKD2L2-DT	XR_948815.3	n.302+871A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOT	ENST00000239926.9	c.1401T>A	p.Asn467Lys	missense_variant	10/10	1	NM_006790.3	ENSP00000239926	P1
PKD2L2-DT	ENST00000514616.6	n.319+871A>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000155 AC: 39 AN: 251450 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135900

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000186 AC: 272 AN: 1461776 Hom.: 0 Cov.: 31 AF XY: 0.000204 AC XY: 148 AN XY: 727182

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000222

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74332

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myofibrillar myopathy 3 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 03, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 467 of the MYOT protein (p.Asn467Lys). This variant is present in population databases (rs145427063, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MYOT-related conditions. ClinVar contains an entry for this variant (Variation ID: 351029). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2017	A variant of uncertain significance has been identified in the MYOT gene. The N467K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N467K variant is observed in 1/6,614 (0.015%) alleles from individuals of Finnish background in large population cohorts (Lek et al., 2016). The N467K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2017	- -

Myofibrillar Myopathy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The c.1401T>A (p.N467K) alteration is located in exon 10 (coding exon 9) of the MYOT gene. This alteration results from a T to A substitution at nucleotide position 1401, causing the asparagine (N) at amino acid position 467 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Limb-Girdle Muscular Dystrophy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.8
DANN	Benign	0.96
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.86	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.40	T
MutationTaster	Benign	0.84	N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.029	D;D;T
Sift4G	Benign	0.076	T;D;D
Vest4		0.47
MutPred		0.33		Gain of MoRF binding (P = 0.0403);.;.;
MVP		0.48
MPC		0.72
ClinPred		0.19	T
GERP RS		-12
gMVP		0.41

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: rs145427063; hg19: chr5-137222978;