17-10629564-TGG-TGGG

Variant names:

• chr17-10629564-T-TG
• rs147333978
• NM_002470.4:c.5796+32dupC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_002470.4(MYH3):​c.5796+32dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000902 in 1,567,810 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (0 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50
• Publications: 0 publications found

Genes affected

MYH3 (HGNC:7573): (myosin heavy chain 3) Myosin is a major contractile protein which converts chemical energy into mechanical energy through the hydrolysis of ATP. Myosin is a hexameric protein composed of a pair of myosin heavy chains (MYH) and two pairs of nonidentical light chains. This gene is a member of the MYH family and encodes a protein with an IQ domain and a myosin head-like domain. Mutations in this gene have been associated with two congenital contracture (arthrogryposis) syndromes, Freeman-Sheldon syndrome and Sheldon-Hall syndrome. [provided by RefSeq, Jul 2008]

MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002470.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	NM_002470.4	MANE Select	c.5796+32dupC		intron	N/A	NP_002461.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	ENST00000583535.6	TSL:5 MANE Select	c.5796+32_5796+33insC		intron	N/A	ENSP00000464317.1
	MYH3	ENST00000577963.1	TSL:2	n.338+32_338+33insC		intron	N/A
	MYHAS	ENST00000579914.2	TSL:4	n.705+15687_705+15688insG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 156 AN: 151642 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.00479

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000442

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.00146 AC: 346 AN: 237438 AF XY: 0.00134

Gnomad AFR exome AF: 0.00451

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.000521

Gnomad EAS exome AF: 0.000819

Gnomad FIN exome AF: 0.000441

Gnomad NFE exome AF: 0.000902

Gnomad OTH exome AF: 0.000860

GnomAD4 exome AF: 0.000888 AC: 1257 AN: 1416056 Hom.: 0 Cov.: 30 AF XY: 0.000951 AC XY: 670 AN XY: 704548

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00312 AC: 96 AN: 30792

American (AMR) AF: 0.00148 AC: 64 AN: 43304

Ashkenazi Jewish (ASJ) AF: 0.000276 AC: 7 AN: 25356

East Asian (EAS) AF: 0.000882 AC: 33 AN: 37432

South Asian (SAS) AF: 0.00365 AC: 303 AN: 83024

European-Finnish (FIN) AF: 0.00116 AC: 60 AN: 51642

Middle Eastern (MID) AF: 0.00122 AC: 5 AN: 4108

European-Non Finnish (NFE) AF: 0.000576 AC: 623 AN: 1082278

Other (OTH) AF: 0.00114 AC: 66 AN: 58120

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00103 AC: 157 AN: 151754 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74212

African (AFR) AF: 0.00228 AC: 94 AN: 41290

American (AMR) AF: 0.000262 AC: 4 AN: 15250

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

East Asian (EAS) AF: 0.000776 AC: 4 AN: 5156

South Asian (SAS) AF: 0.00479 AC: 23 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000442 AC: 30 AN: 67910

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.00310 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5
Mutation Taster		=100/0	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: rs147333978; hg19: chr17-10532881; COSMIC: COSV56870533;