rs34613390

Positions:

• chr17-10415580-G-A
• chr17-10415580-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002472.3(MYH8):​c.540C>T​(p.Thr180=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00076 in 1,614,076 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (3 hom.)
• Consequence: MYH8 NM_002472.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.00003167
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.37

Genes affected

MYH8 (HGNC:7578): (myosin heavy chain 8) Myosins are actin-based motor proteins that function in the generation of mechanical force in eukaryotic cells. Muscle myosins are heterohexamers composed of 2 myosin heavy chains and 2 pairs of nonidentical myosin light chains. This gene encodes a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction. This gene is predominantly expressed in fetal skeletal muscle. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in trismus-pseudocamptodactyly syndrome. [provided by RefSeq, Sep 2009]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-10415580-G-A is Benign according to our data. Variant chr17-10415580-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 211568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10415580-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.37 with no splicing effect.
• BS2: High AC in GnomAd4 at 513 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH8	NM_002472.3	c.540C>T	p.Thr180=	splice_region_variant, synonymous_variant	7/40	ENST00000403437.2
MYHAS	NR_125367.1	n.167+9342G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH8	ENST00000403437.2	c.540C>T	p.Thr180=	splice_region_variant, synonymous_variant	7/40	5	NM_002472.3	P1
	ENST00000399342.6	n.206+9303G>A		intron_variant, non_coding_transcript_variant		3
	ENST00000581304.1	n.143+9342G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152126 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00118 AC: 296 AN: 251320 Hom.: 1 AF XY: 0.00105 AC XY: 142 AN XY: 135806

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000488 AC: 713 AN: 1461832 Hom.: 3 Cov.: 34 AF XY: 0.000491 AC XY: 357 AN XY: 727230

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00337 AC: 513 AN: 152244 Hom.: 2 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74440

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000792 Hom.: 2

Bravo AF: 0.00365

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 02, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.0060
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0040
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: rs34613390; hg19: chr17-10318897;