NM_002470.4:c.774G>A

Variant names:

• chr17-10647388-C-T
• rs16943598
• NM_002470.4:c.774G>A

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_002470.4(MYH3):​c.774G>A​(p.Lys258Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,614,232 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (17 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0810
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 17-10647388-C-T is Benign according to our data. Variant chr17-10647388-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.081 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00721 (1099/152354) while in subpopulation AFR AF = 0.0248 (1031/41582). AF 95% confidence interval is 0.0235. There are 12 homozygotes in GnomAd4. There are 556 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.774G>A	p.Lys258Lys	synonymous	Exon 9 of 41	NP_002461.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	ENST00000583535.6	TSL:5 MANE Select	c.774G>A	p.Lys258Lys	synonymous	Exon 9 of 41	ENSP00000464317.1
	MYH3	ENST00000961194.1		c.774G>A	p.Lys258Lys	synonymous	Exon 8 of 40	ENSP00000631253.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+33511C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00719 AC: 1094 AN: 152236 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00188 AC: 471 AN: 251148 AF XY: 0.00135

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000819 AC: 1197 AN: 1461878 Hom.: 17 Cov.: 32 AF XY: 0.000653 AC XY: 475 AN XY: 727238

African (AFR) AF: 0.0259 AC: 866 AN: 33480

American (AMR) AF: 0.00190 AC: 85 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.000112 AC: 125 AN: 1112010

Other (OTH) AF: 0.00166 AC: 100 AN: 60396

GnomAD4 genome AF: 0.00721 AC: 1099 AN: 152354 Hom.: 12 Cov.: 33 AF XY: 0.00746 AC XY: 556 AN XY: 74504

African (AFR) AF: 0.0248 AC: 1031 AN: 41582

American (AMR) AF: 0.00333 AC: 51 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68034

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00360 Hom.: 7

Bravo AF: 0.00869

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Distal arthrogryposis type 2B1 (1)
-	-	1	Freeman-Sheldon syndrome (1)
-	-	1	MYH3-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	10
DANN	Benign	0.60
PhyloP100		-0.081
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs16943598; hg19: chr17-10550705;