rs760217241

Variant names:

• chr5-137880867-TA-T
• rs760217241
• NM_006790.3:c.683+8delA

Your query was ambiguous. Multiple possible variants found:

• chr5-137880867-TA-T
• chr5-137880867-TA-TAA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_006790.3(MYOT):​c.683+8delA variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000144 in 1,592,444 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: MYOT NM_006790.3 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.81
• 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 5-137880867-TA-T is Benign according to our data. Variant chr5-137880867-TA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 464375.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000282 (43/152326) while in subpopulation AFR AF = 0.000625 (26/41582). AF 95% confidence interval is 0.000438. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 43 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.683+8delA		splice_region intron	N/A	NP_006781.1	A0A0C4DFM5
	MYOT	NM_001300911.2		c.338+8delA		splice_region intron	N/A	NP_001287840.1	B4DT68
	MYOT	NM_001135940.2		c.131+8delA		splice_region 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.683+8delA		splice_region intron	N/A	ENSP00000239926.4	A0A0C4DFM5
	MYOT	ENST00000968642.1		c.683+8delA		splice_region intron	N/A	ENSP00000638701.1
	MYOT	ENST00000968644.1		c.678+13delA		intron	N/A	ENSP00000638703.1

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000143 AC: 35 AN: 244384 AF XY: 0.000106

Gnomad AFR exome AF: 0.000446

Gnomad AMR exome AF: 0.000382

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.000500

GnomAD4 exome AF: 0.000130 AC: 187 AN: 1440118 Hom.: 0 Cov.: 26 AF XY: 0.000120 AC XY: 86 AN XY: 717346

African (AFR) AF: 0.000334 AC: 11 AN: 32978

American (AMR) AF: 0.000383 AC: 17 AN: 44402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 39430

South Asian (SAS) AF: 0.00 AC: 0 AN: 85082

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53194

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5720

European-Non Finnish (NFE) AF: 0.000126 AC: 138 AN: 1093760

Other (OTH) AF: 0.000319 AC: 19 AN: 59614

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74496

African (AFR) AF: 0.000625 AC: 26 AN: 41582

American (AMR) AF: 0.000458 AC: 7 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000412

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Myofibrillar myopathy 3 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=74/26	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: rs760217241; hg19: chr5-137216556;