rs141801816

Variant names:

• chr5-137887252-G-A
• rs141801816
• NM_006790.3:c.1364G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-137887252-G-A
• chr5-137887252-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_006790.3(MYOT):​c.1364G>A​(p.Arg455Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000039 in 1,613,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R455W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: MYOT NM_006790.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 4.21
• Publications: 2 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09365642).
• BP6: Variant 5-137887252-G-A is Benign according to our data. Variant chr5-137887252-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 583005.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000151 (23/152048) while in subpopulation AFR AF = 0.000531 (22/41400). AF 95% confidence interval is 0.000359. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 23 AD gene.

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.1364G>A	p.Arg455Gln	missense	Exon 10 of 10	NP_006781.1	A0A0C4DFM5
	MYOT	NM_001300911.2		c.1019G>A	p.Arg340Gln	missense	Exon 11 of 11	NP_001287840.1	B4DT68
	MYOT	NM_001135940.2		c.812G>A	p.Arg271Gln	missense	Exon 10 of 10	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.1364G>A	p.Arg455Gln	missense	Exon 10 of 10	ENSP00000239926.4	A0A0C4DFM5
	MYOT	ENST00000968642.1		c.1361G>A	p.Arg454Gln	missense	Exon 10 of 10	ENSP00000638701.1
	MYOT	ENST00000968644.1		c.1226G>A	p.Arg409Gln	missense	Exon 8 of 8	ENSP00000638703.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000875 AC: 22 AN: 251436 AF XY: 0.0000736

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20 AN XY: 727180

African (AFR) AF: 0.000717 AC: 24 AN: 33478

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111944

Other (OTH) AF: 0.0000497 AC: 3 AN: 60392

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74274

African (AFR) AF: 0.000531 AC: 22 AN: 41400

American (AMR) AF: 0.0000656 AC: 1 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000329 Hom.: 0

Bravo AF: 0.000200

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Myofibrillar myopathy 3 (2)
-	-	2	not provided (2)
-	1	-	Cardiomyopathy (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Pathogenic	1.0
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.79	T
PhyloP100		4.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.16
Sift	Benign	0.059	T
Sift4G	Uncertain	0.021	D
Vest4		0.32
MVP		0.89
MPC		0.32
ClinPred		0.064	T
GERP RS		5.8
gMVP		0.38
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs141801816; hg19: chr5-137222941;