chr5-137883548-T-C

Variant names:

• chr5-137883548-T-C
• rs148479015
• NM_006790.3:c.981T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_006790.3(MYOT):​c.981T>C​(p.Asn327Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00078 in 1,614,116 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (4 hom.)
• Consequence: MYOT NM_006790.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0590
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 5-137883548-T-C is Benign according to our data. Variant chr5-137883548-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.059 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00131 (200/152252) while in subpopulation AMR AF = 0.00118 (18/15282). AF 95% confidence interval is 0.000761. There are 4 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 200 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.981T>C	p.Asn327Asn	synonymous	Exon 7 of 10	NP_006781.1	A0A0C4DFM5
	MYOT	NM_001300911.2		c.636T>C	p.Asn212Asn	synonymous	Exon 8 of 11	NP_001287840.1	B4DT68
	MYOT	NM_001135940.2		c.429T>C	p.Asn143Asn	synonymous	Exon 7 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.981T>C	p.Asn327Asn	synonymous	Exon 7 of 10	ENSP00000239926.4	A0A0C4DFM5
	MYOT	ENST00000968642.1		c.978T>C	p.Asn326Asn	synonymous	Exon 7 of 10	ENSP00000638701.1
	MYOT	ENST00000968644.1		c.843T>C	p.Asn281Asn	synonymous	Exon 5 of 8	ENSP00000638703.1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152134 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000958 AC: 241 AN: 251452 AF XY: 0.000868

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000888

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.000724 AC: 1059 AN: 1461864 Hom.: 4 Cov.: 31 AF XY: 0.000770 AC XY: 560 AN XY: 727228

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.00134 AC: 60 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00593 AC: 155 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000696 AC: 60 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

Middle Eastern (MID) AF: 0.0217 AC: 125 AN: 5768

European-Non Finnish (NFE) AF: 0.000472 AC: 525 AN: 1111998

Other (OTH) AF: 0.00179 AC: 108 AN: 60394

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152252 Hom.: 4 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74472

African (AFR) AF: 0.000746 AC: 31 AN: 41550

American (AMR) AF: 0.00118 AC: 18 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68006

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00168

EpiCase AF: 0.00191

EpiControl AF: 0.00148

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Myofibrillar myopathy 3 (2)
-	-	1	Limb-Girdle Muscular Dystrophy, Dominant (1)
-	-	1	Myofibrillar Myopathy, Dominant (1)
-	-	1	MYOT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	3.2
DANN	Benign	0.74
PhyloP100		0.059
Mutation Taster		=93/7	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: rs148479015; hg19: chr5-137219237;