NM_002470.4:c.2683-14C>A

Variant names:

• chr17-10639816-G-T
• rs202129717
• NM_002470.4:c.2683-14C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002470.4(MYH3):​c.2683-14C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000762 in 1,610,814 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00078 (3 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.934
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 17-10639816-G-T is Benign according to our data. Variant chr17-10639816-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 321746.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000778 (1135/1459120) while in subpopulation MID AF = 0.012 (69/5760). AF 95% confidence interval is 0.00971. There are 3 homozygotes in GnomAdExome4. There are 569 alleles in the male GnomAdExome4 subpopulation. Median coverage is 41. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

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.2683-14C>A		intron	N/A	NP_002461.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	ENST00000583535.6	TSL:5 MANE Select	c.2683-14C>A		intron	N/A	ENSP00000464317.1
	MYH3	ENST00000961194.1		c.2683-14C>A		intron	N/A	ENSP00000631253.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+25939G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000614 AC: 93 AN: 151576 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000677

Gnomad OTH AF: 0.000963

GnomAD2 exomes AF: 0.000487 AC: 122 AN: 250338 AF XY: 0.000583

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000663

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000778 AC: 1135 AN: 1459120 Hom.: 3 Cov.: 41 AF XY: 0.000784 AC XY: 569 AN XY: 726020

African (AFR) AF: 0.000389 AC: 13 AN: 33418

American (AMR) AF: 0.000380 AC: 17 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26122

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39688

South Asian (SAS) AF: 0.000603 AC: 52 AN: 86184

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53258

Middle Eastern (MID) AF: 0.0120 AC: 69 AN: 5760

European-Non Finnish (NFE) AF: 0.000804 AC: 892 AN: 1109680

Other (OTH) AF: 0.00101 AC: 61 AN: 60308

GnomAD4 genome AF: 0.000606 AC: 92 AN: 151694 Hom.: 0 Cov.: 31 AF XY: 0.000513 AC XY: 38 AN XY: 74106

African (AFR) AF: 0.000315 AC: 13 AN: 41326

American (AMR) AF: 0.00151 AC: 23 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000626 AC: 3 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10478

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000677 AC: 46 AN: 67932

Other (OTH) AF: 0.000953 AC: 2 AN: 2098

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.000918

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Distal arthrogryposis type 2B1 (1)
-	-	1	Freeman-Sheldon syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.019
DANN	Benign	0.34
PhyloP100		-0.93
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs202129717; hg19: chr17-10543133;