rs2285467

Variant names:

• chr17-10651704-T-C
• rs2285467
• NM_002470.4:c.349-36A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002470.4(MYH3):​c.349-36A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,605,336 control chromosomes in the GnomAD database, including 14,728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1312 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13416 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.427
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-10651704-T-C is Benign according to our data. Variant chr17-10651704-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	NM_002470.4	MANE Select	c.349-36A>G		intron	N/A	NP_002461.2	P11055

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	ENST00000583535.6	TSL:5 MANE Select	c.349-36A>G		intron	N/A	ENSP00000464317.1	P11055
	MYH3	ENST00000961194.1		c.349-36A>G		intron	N/A	ENSP00000631253.1
	MYH3	ENST00000579489.2	TSL:5	n.265A>G		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19448 AN: 151322 Hom.: 1311 Cov.: 31

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.0403

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.122

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.139

GnomAD2 exomes AF: 0.121 AC: 30290 AN: 250760 AF XY: 0.125

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0693

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.0410

Gnomad FIN exome AF: 0.134

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.133 AC: 193256 AN: 1453916 Hom.: 13416 Cov.: 34 AF XY: 0.134 AC XY: 96943 AN XY: 723818

African (AFR) AF: 0.121 AC: 4024 AN: 33298

American (AMR) AF: 0.0739 AC: 3302 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3683 AN: 26058

East Asian (EAS) AF: 0.0362 AC: 1437 AN: 39654

South Asian (SAS) AF: 0.133 AC: 11482 AN: 86124

European-Finnish (FIN) AF: 0.131 AC: 7010 AN: 53360

Middle Eastern (MID) AF: 0.148 AC: 849 AN: 5746

European-Non Finnish (NFE) AF: 0.139 AC: 153330 AN: 1104874

Other (OTH) AF: 0.135 AC: 8139 AN: 60116

GnomAD4 genome AF: 0.128 AC: 19446 AN: 151420 Hom.: 1312 Cov.: 31 AF XY: 0.128 AC XY: 9439 AN XY: 73894

African (AFR) AF: 0.122 AC: 5054 AN: 41260

American (AMR) AF: 0.114 AC: 1735 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 471 AN: 3468

East Asian (EAS) AF: 0.0408 AC: 210 AN: 5148

South Asian (SAS) AF: 0.129 AC: 620 AN: 4792

European-Finnish (FIN) AF: 0.129 AC: 1328 AN: 10318

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 290

European-Non Finnish (NFE) AF: 0.141 AC: 9578 AN: 67932

Other (OTH) AF: 0.137 AC: 287 AN: 2090

Alfa AF: 0.134 Hom.: 340

Bravo AF: 0.125

Asia WGS AF: 0.0980 AC: 340 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Arthrogryposis, distal, type 2B3 (1)
-	-	1	Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A (1)
-	-	1	Contractures, pterygia, and variable skeletal fusions syndrome 1B (1)
-	-	1	Freeman-Sheldon syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.7
DANN	Benign	0.24
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism (auto)

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: rs2285467; hg19: chr17-10555021;