NM_002470.4:c.4956+32C>T

Variant names:

• chr17-10632444-G-A
• rs4792008
• NM_002470.4:c.4956+32C>T

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.4956+32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,604,222 control chromosomes in the GnomAD database, including 377,489 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (27810 hom., cov: 33)
  • Exomes 𝑓: 0.69 (349679 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0540
• Publications: 9 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]

LOC124903927 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-10632444-G-A is Benign according to our data. Variant chr17-10632444-G-A is described in ClinVar as Benign. ClinVar VariationId is 258690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.728 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.4956+32C>T		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.4956+32C>T		intron	N/A	ENSP00000464317.1	P11055
	MYH3	ENST00000961194.1		c.4956+32C>T		intron	N/A	ENSP00000631253.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+18567G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.573 AC: 87100 AN: 152014 Hom.: 27808 Cov.: 33

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.703

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.589

GnomAD2 exomes AF: 0.607 AC: 148956 AN: 245230 AF XY: 0.620

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.707

Gnomad EAS exome AF: 0.362

Gnomad FIN exome AF: 0.714

Gnomad NFE exome AF: 0.727

Gnomad OTH exome AF: 0.652

GnomAD4 exome AF: 0.686 AC: 995503 AN: 1452090 Hom.: 349679 Cov.: 33 AF XY: 0.684 AC XY: 494676 AN XY: 722910

African (AFR) AF: 0.277 AC: 9241 AN: 33372

American (AMR) AF: 0.479 AC: 21435 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 18395 AN: 26112

East Asian (EAS) AF: 0.367 AC: 14568 AN: 39682

South Asian (SAS) AF: 0.540 AC: 46541 AN: 86142

European-Finnish (FIN) AF: 0.719 AC: 34287 AN: 47664

Middle Eastern (MID) AF: 0.563 AC: 2943 AN: 5224

European-Non Finnish (NFE) AF: 0.729 AC: 808831 AN: 1109004

Other (OTH) AF: 0.652 AC: 39262 AN: 60184

GnomAD4 genome AF: 0.573 AC: 87125 AN: 152132 Hom.: 27810 Cov.: 33 AF XY: 0.568 AC XY: 42234 AN XY: 74356

African (AFR) AF: 0.295 AC: 12254 AN: 41496

American (AMR) AF: 0.561 AC: 8581 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.703 AC: 2442 AN: 3472

East Asian (EAS) AF: 0.371 AC: 1917 AN: 5174

South Asian (SAS) AF: 0.523 AC: 2524 AN: 4822

European-Finnish (FIN) AF: 0.706 AC: 7470 AN: 10578

Middle Eastern (MID) AF: 0.545 AC: 159 AN: 292

European-Non Finnish (NFE) AF: 0.733 AC: 49855 AN: 67984

Other (OTH) AF: 0.589 AC: 1245 AN: 2114

Alfa AF: 0.653 Hom.: 15053

Bravo AF: 0.547

Asia WGS AF: 0.448 AC: 1564 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.82
CADD	Benign	1.8
DANN	Benign	0.73
PhyloP100		0.054
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: rs4792008; hg19: chr17-10535761; COSMIC: COSV56865868; COSMIC: COSV56865868;