17-10650374-G-T

Variant names:

• chr17-10650374-G-T
• rs121913619
• NM_002470.4:c.533C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Strong

The NM_002470.4(MYH3):​c.533C>A​(p.Thr178Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T178I) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYH3 NM_002470.4 missense, splice_region
• Scores: Splicing: ADA: 0.8403
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-10650374-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in the MYH3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 1.7445 (below the threshold of 3.09). Trascript score misZ: 4.649 (above the threshold of 3.09). GenCC associations: The gene is linked to spondylocarpotarsal synostosis syndrome, contractures, pterygia, and variable skeletal fusions syndrome 1B, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, digitotalar dysmorphism, autosomal recessive multiple pterygium syndrome, Freeman-Sheldon syndrome, distal arthrogryposis type 2B1, Sheldon-hall syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.533C>A	p.Thr178Asn	missense_variant, splice_region_variant	Exon 6 of 41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.533C>A	p.Thr178Asn	missense_variant, splice_region_variant	Exon 6 of 41		XP_011522172.1
MYH3	XM_011523871.3	c.533C>A	p.Thr178Asn	missense_variant, splice_region_variant	Exon 6 of 41		XP_011522173.1
MYH3	XM_047436127.1	c.533C>A	p.Thr178Asn	missense_variant, splice_region_variant	Exon 8 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.533C>A	p.Thr178Asn	missense_variant, splice_region_variant	Exon 6 of 41	5	NM_002470.4	ENSP00000464317.1
MYH3	ENST00000579489.2	n.485C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251260 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459598 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726308

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PrimateAI	Pathogenic	0.92	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.68		Loss of sheet (P = 0.1158);
MVP		0.93
MPC		2.0
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.90
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.84
dbscSNV1_RF	Pathogenic	0.78
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

Publications

LitVar

Other links and lift over

dbSNP: rs121913619; hg19: chr17-10553691;