17-10648602-G-C

Variant names:

• chr17-10648602-G-C
• rs147148934
• NM_002470.4:c.690C>G

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.690C>G​(p.Ala230Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 1,613,692 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A230A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0044 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (38 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.44
• Publications: 4 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=-0.46).
• BP6: Variant 17-10648602-G-C is Benign according to our data. Variant chr17-10648602-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00501 (7319/1461434) while in subpopulation MID AF = 0.0163 (94/5762). AF 95% confidence interval is 0.0136. There are 38 homozygotes in GnomAdExome4. There are 3723 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.690C>G	p.Ala230Ala	synonymous	Exon 8 of 41	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.690C>G	p.Ala230Ala	synonymous	Exon 8 of 41	ENSP00000464317.1	P11055
	MYH3	ENST00000961194.1		c.690C>G	p.Ala230Ala	synonymous	Exon 7 of 40	ENSP00000631253.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+34725G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00436 AC: 664 AN: 152140 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00510

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00504 AC: 1267 AN: 251492 AF XY: 0.00567

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00572

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00501 AC: 7319 AN: 1461434 Hom.: 38 Cov.: 31 AF XY: 0.00512 AC XY: 3723 AN XY: 727036

African (AFR) AF: 0.00188 AC: 63 AN: 33476

American (AMR) AF: 0.00356 AC: 159 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 460 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00850 AC: 733 AN: 86244

European-Finnish (FIN) AF: 0.00129 AC: 69 AN: 53414

Middle Eastern (MID) AF: 0.0163 AC: 94 AN: 5762

European-Non Finnish (NFE) AF: 0.00486 AC: 5400 AN: 1111610

Other (OTH) AF: 0.00563 AC: 340 AN: 60380

GnomAD4 genome AF: 0.00437 AC: 665 AN: 152258 Hom.: 2 Cov.: 32 AF XY: 0.00435 AC XY: 324 AN XY: 74460

African (AFR) AF: 0.00245 AC: 102 AN: 41554

American (AMR) AF: 0.00641 AC: 98 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3470

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

South Asian (SAS) AF: 0.00809 AC: 39 AN: 4820

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10614

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00512 AC: 348 AN: 68026

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00691 Hom.: 4

Bravo AF: 0.00491

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00692

EpiControl AF: 0.00622

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	Distal arthrogryposis type 2B1 (1)
-	-	1	Freeman-Sheldon syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.75
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	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: rs147148934; hg19: chr17-10551919;