rs557849165

Variant names:

• chr17-10656089-C-T
• rs557849165
• NM_002470.4:c.-9+1G>A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_002470.4(MYH3):​c.-9+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 152,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH3 NM_002470.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 2.73

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.7, offset of -13, new splice context is: cagGTggga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 17-10656089-C-T is Pathogenic according to our data. Variant chr17-10656089-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 587706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10656089-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-10656089-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.-9+1G>A		splice_donor_variant, intron_variant	Intron 2 of 40	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.-9+1G>A		splice_donor_variant, intron_variant	Intron 2 of 40		XP_011522172.1
MYH3	XM_011523871.3	c.-9+1G>A		splice_donor_variant, intron_variant	Intron 2 of 40		XP_011522173.1
MYH3	XM_047436127.1	c.-9+1G>A		splice_donor_variant, intron_variant	Intron 4 of 42		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.-9+1G>A		splice_donor_variant, intron_variant	Intron 2 of 40	5	NM_002470.4	ENSP00000464317.1
MYH3	ENST00000582580.1	n.80+1G>A		splice_donor_variant, intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.000956

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 80 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 60

Gnomad4 AFR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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 AF: 0.00114 AC: 173 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.00130 AC XY: 97 AN XY: 74472

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00754

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00222 Hom.: 0

Bravo AF: 0.000499

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the MYH3 gene. It does not change the encoded amino acid sequence of the MYH3 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs557849165, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with clinical features of autosomal recessive MYH3-related conditions (PMID: 29805041, 32902138; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 587706). Studies have shown that this variant alters MYH3 gene expression (PMID: 29805041). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 2, but is expected to preserve the integrity of the reading-frame (PMID: 29805041). For these reasons, this variant has been classified as Pathogenic. -

Sep 15, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYH3: PM3:Strong, PM2:Supporting, PS3:Supporting -

Feb 24, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RNA studies demonstrate a damaging effect resulting in reduction of translational efficiency (PMID: 29805041); Reported with a second MYH3 variant in patients with complex skeletal anomalies (PMID: 35169139, 37273706); This variant is associated with the following publications: (PMID: 32902138, 34440395, 33726816, Sergi2022[casereport], 34204301, 38444278, 29805041, 37273706, 35169139) -

MYH3-related disorder Pathogenic:3

Aug 08, 2023

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYH3 c.-9+1G>A variant results in a substitution at a consensus splice donor site that has been shown to result in abnormal splicing with an increase in transcripts lacking exon 2 (PMID: 29805041). This variant was identified in a compound heterozygous state in at least 9 individuals with spondylocarpotarsal synostosis, multiple pterygium syndrome (MPS), and vertebral fusions, arthrogryposis and multiple pterygia (PMID: 29805041; 34440395; 35169139). The highest frequency of this allele in the Genome Aggregation Database is 0.010640 in the European (Finnish) population, however, this variant is not found in the homozygous state but is flagged as low confidence (version 2.1.1). Functional studies conducted in human cell lines demonstrated that transcripts containing the c.-9+1G>A variant lacking exon 2 display a reduced translational efficiency of 54% compared to wild-type (PMID: 29805041). Based on the available evidence, the c.-9+1G>A variant is classified as likely pathogenic for MYH3-related disorders. -

Dec 23, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH3 c.-9+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 prime splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and results in loss of part of 5'-UTR sequence (Cameron-Christie_2018). The variant allele was found at a frequency of 0.0027 in 31404 control chromosomes. c.-9+1G>A has been reported in the literature and found in our internal database in individuals affected with MYH3-Related Disorders in compound heterozygous or heterozygous status. These reports do not provide unequivocal conclusions about association of the variant with MYH3-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function. This variant leads to a translational efficiency of 54% relative to that of the wild-type (Cameron-Christie_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic n=3, VUS n=1, Benign n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jan 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MYH3 c.-9+1G>A variant is located in the 5' untranslated region. This variant has been reported in the compound heterozygous state in at least six individuals from three different families with autosomal recessive spondylocarpotarsal synostosis syndrome (Cameron-Christie et al 2018. PubMed ID: 29805041). This variant was also detected in the compound heterozygous state in patients with MYH3-associated conditions (Hakonen et al. 2020. PubMed ID: 32902138; Dahan-Oliel et al. 2021. PubMed ID: 34440395; Zhao et al. 2022. PubMed ID: 35169139). In addition, functional evidence supports that this variant results in aberrant splicing and reduced translational efficiency (Cameron-Christie et al 2018. PubMed ID: 29805041). Although this variant has an allele frequency up to 1.1% in Finnish Europeans, this variant is suggested to be a hypomorphic allele. In summary, this variant is interpreted as likely pathogenic. -

Contractures, pterygia, and variable skeletal fusions syndrome 1B Pathogenic:3

Feb 27, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant affects the canonical donor splice site at the untranslated boundary between exon 2 and intron 2, leading to reduced translational efficiency (Zhao et a., 2022). -

Dec 19, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.274%). Predicted Consequence/Location: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000587706 /PMID: 29805041). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Spondylocarpotarsal synostosis syndrome;C1867440:Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A Pathogenic:1

Apr 09, 2018

Clinical Genetics Group, University of Otago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A Pathogenic:1

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

NG_011537.1(NM_002470.3):c.-9+1G>A in the MYH3 gene has an allele frequency of 0.011 in European(Finnish) subpopulation in the gnomAD database. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was detected in multiple individuals with autosomal recessive Spondylocarpotarsal Synostosis Syndrome, compound heterozygous with c.4647+1G>A, c.141T>G, deletion of intron 12 and exon 25 (PMID: 29805041).Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PM3_Strong. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Uncertain	0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.92		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs557849165; hg19: chr17-10559406;