rs1555527172

Variant names:

• chr17-10648586-T-G
• rs1555527172
• NM_002470.4:c.706A>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_002470.4(MYH3):​c.706A>C​(p.Thr236Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH3 NM_002470.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.27
• 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_002470.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 17-10648586-T-G is Pathogenic according to our data. Variant chr17-10648586-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 520870.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.706A>C	p.Thr236Pro	missense_variant	Exon 8 of 41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.706A>C	p.Thr236Pro	missense_variant	Exon 8 of 41		XP_011522172.1
MYH3	XM_011523871.3	c.706A>C	p.Thr236Pro	missense_variant	Exon 8 of 41		XP_011522173.1
MYH3	XM_047436127.1	c.706A>C	p.Thr236Pro	missense_variant	Exon 10 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.706A>C	p.Thr236Pro	missense_variant	Exon 8 of 41	5	NM_002470.4	ENSP00000464317.1
MYHAS	ENST00000579914.2	n.705+34709T>G		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2	n.1042-32147T>G		intron_variant	Intron 7 of 8	3
MYH3	ENST00000579489.2	n.*49A>C		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

May 31, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	5.0	H
PhyloP100		6.3
PrimateAI	Pathogenic	0.80	T
Sift4G	Pathogenic	0.0010	D
Vest4		0.82
ClinPred		0.96	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.92

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: rs1555527172; hg19: chr17-10551903;