rs200954595

Variant names:

• chr17-10630285-C-T
• rs200954595
• NM_002470.4:c.5457+3G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002470.4(MYH3):​c.5457+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0324 in 1,614,084 control chromosomes in the GnomAD database, including 1,002 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (65 hom., cov: 32)
  • Exomes 𝑓: 0.033 (937 hom.)
• Consequence: MYH3 NM_002470.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002457
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.596
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 17-10630285-C-T is Benign according to our data. Variant chr17-10630285-C-T is described in ClinVar as Benign. ClinVar VariationId is 129665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0237 (3609/152200) while in subpopulation NFE AF = 0.0373 (2539/68002). AF 95% confidence interval is 0.0361. There are 65 homozygotes in GnomAd4. There are 1735 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 65 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	NM_002470.4	MANE Select	c.5457+3G>A		splice_region 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.5457+3G>A		splice_region intron	N/A	ENSP00000464317.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+16408C>T		intron	N/A
	MYHAS	ENST00000584139.2	TSL:3	n.1041+16408C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3611 AN: 152082 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.00657

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.0405

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0373

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0242 AC: 6089 AN: 251484 AF XY: 0.0245

Gnomad AFR exome AF: 0.00689

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.00764

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0425

Gnomad NFE exome AF: 0.0361

Gnomad OTH exome AF: 0.0283

GnomAD4 exome AF: 0.0333 AC: 48633 AN: 1461884 Hom.: 937 Cov.: 35 AF XY: 0.0327 AC XY: 23808 AN XY: 727240

African (AFR) AF: 0.00514 AC: 172 AN: 33480

American (AMR) AF: 0.0107 AC: 479 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00846 AC: 221 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0113 AC: 976 AN: 86258

European-Finnish (FIN) AF: 0.0431 AC: 2303 AN: 53420

Middle Eastern (MID) AF: 0.0219 AC: 126 AN: 5764

European-Non Finnish (NFE) AF: 0.0384 AC: 42658 AN: 1112008

Other (OTH) AF: 0.0281 AC: 1696 AN: 60394

GnomAD4 genome AF: 0.0237 AC: 3609 AN: 152200 Hom.: 65 Cov.: 32 AF XY: 0.0233 AC XY: 1735 AN XY: 74424

African (AFR) AF: 0.00655 AC: 272 AN: 41552

American (AMR) AF: 0.0159 AC: 243 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4824

European-Finnish (FIN) AF: 0.0405 AC: 429 AN: 10582

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0373 AC: 2539 AN: 68002

Other (OTH) AF: 0.0194 AC: 41 AN: 2112

Alfa AF: 0.0302 Hom.: 38

Bravo AF: 0.0206

Asia WGS AF: 0.00578 AC: 20 AN: 3476

EpiCase AF: 0.0329

EpiControl AF: 0.0341

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	-0.64
CADD	Benign	8.4
DANN	Benign	0.79
PhyloP100		0.60
Mutation Taster		=18/82	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.088
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: rs200954595; hg19: chr17-10533602;