chr16-15708829-TG-T

Position:

• chr16-15708829-TG-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Moderate PP5

The ENST00000452625.7(MYH11):​c.5819del​(p.Pro1940HisfsTer91) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000963 in 1,453,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MYH11 ENST00000452625.7 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 1.54

Genes affected

MYH11 (HGNC:7569): (myosin heavy chain 11) The protein encoded by this gene is a smooth muscle myosin belonging to the myosin heavy chain family. The gene product is a subunit of a hexameric protein that consists of two heavy chain subunits and two pairs of non-identical light chain subunits. It functions as a major contractile protein, converting chemical energy into mechanical energy through the hydrolysis of ATP. A chromosomal rearrangement involving this gene is associated with acute myeloid leukemia of the M4Eo subtype. Mutations in this gene are associated with visceral myopathy, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, and familial thoracic aortic aneurysm 4. [provided by RefSeq, May 2022]

NDE1 (HGNC:17619): (nudE neurodevelopment protein 1) This gene encodes a member of the nuclear distribution E (NudE) family of proteins. The encoded protein is localized at the centrosome and interacts with other centrosome components as part of a multiprotein complex that regulates dynein function. This protein plays an essential role in microtubule organization, mitosis and neuronal migration. Mutations in this gene cause lissencephaly 4, a disorder characterized by lissencephaly, severe brain atrophy, microcephaly, and severe cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00325 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PP5: Variant 16-15708829-TG-T is Pathogenic according to our data. Variant chr16-15708829-TG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 627645.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_001040113.2	c.5819del	p.Pro1940HisfsTer91	frameshift_variant	42/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_002474.3	c.5787-4707del		intron_variant		ENST00000300036.6	NP_002465.1
NDE1	NM_017668.3	c.947+11977del		intron_variant		ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000452625.7	c.5819del	p.Pro1940HisfsTer91	frameshift_variant	42/43	1	NM_001040113.2	ENSP00000407821
MYH11	ENST00000300036.6	c.5787-4707del		intron_variant		1	NM_002474.3	ENSP00000300036	P3
NDE1	ENST00000396354.6	c.947+11977del		intron_variant		1	NM_017668.3	ENSP00000379642	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000963 AC: 14 AN: 1453882 Hom.: 0 Cov.: 32 AF XY: 0.00000969 AC XY: 7 AN XY: 722754

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000683

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000354

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000632

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Visceral myopathy 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	-	The p.Pro1940Hisfs*91 variant detected here only impacts isoform SM2. It occurs in the last coding exon (exon 42 of 43, NM_001040113) and results in a frameshift at position 1940, 5 amino acids away from the canonical stop codon. It is predicted to cause protein elongation followed by a stop codon after 91 amino acids. The p.Pro1940Hisfs*91 variant is also present in large population studies at low frequencies (14 of 1,605,644 alleles, gnomAD v4.1.0). The p.Pro1940Hisfs*91 variant has been reported in individuals with gastrointestinal dysmotility. In one family with a history of chronic intestinal pseudo-obstruction (CIPO), seven affected family members were found to be heterozygous for the variant. Three unaffected family members were negative for the variant. Clinical findings reported in the affected individuals included megacystis, bowel obstruction, rectal prolapse, and malrotation (PMID: 31389005, family RQ6654). An unrelated individual was also found to be heterozygous for this variant (PMID: 31944481, family 2). She presented in infancy with constipation and was diagnosed with intestinal pseudo-obstruction at age 11. Several other family members had histories of a chronic intestinal motility disorder, but genetic testing was not performed. A nearby variant also predicted to result in MYH11 elongation has also been reported in family with multiple similarly affected individuals (PMID: 31944481, family 1). -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 05, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 28, 2021	- -

Chronic intestinal pseudoobstruction Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS). CIPO and familial thoracic aortic aneurysm 4 (MIM#132900) are caused by variants of unknown mechanism. Dominant negative is a suggested mechanism of disease (PMID: 31389005, PMID: 31944481). (I) 0108 - This gene is associated with both recessive and dominant disease. MMIHS is a recessive form of disease caused by both missense variants and those resulting in a premature termination codon. Familial thoracic aortic aneurysm 4 has been reported in patients with splice, missense and inframe deletion variants. CIPO has only been reported in patients with protein elongation variants exclusive to isoform SM2 (PMID: 31389005, PMID: 31944481). (I) 0208 - Variant is predicted to result in an elongated protein. (SP) 0219 - This variant is non-coding in an alternative transcript. This variant is non-coding in the predominantly reported transcript (ClinVar), but is protein coding in isoform SM2 (NCBI, UCSC). (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (16 heterozygotes, 0 homozygotes) however, the region has low quality. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another protein elongation variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This variant (p.Gln1941Asnfs*91) has been reported as likely pathogenic and observed in a single family with a dysmotility syndrome with severe esophageal, gastric and intestinal disease. It has also been described as likely benign for aortic aneurysm (PMID: 31944481, ClinVar). An additional protein elongation variant (p.Gln1941Thrfs*20) has been reported as likely benign, a VUS and benign however, this classification is in reference to an aortopathy phenotype only (ClinVar). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as both a VUS and likely pathogenic (ClinVar, LOVD), but has been reported in a large family with CIPO and a single patient with severe esophageal, gastric and colonic dysmotility (PMID: 31389005, PMID: 31944481). (I) 0901 - This variant has strong evidence for segregation with disease. This variant was observed in seven affected patients in a single family with chronic intestinal pseudo-obstruction (CIPO) (PMID: 31389005). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies demonstrated that while wildtype actin was only motile when phosphorylated, mutant actin expressing this variant was observed to be motile when both phosphorylated and unphosphorylated (PMID: 18391202). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, no assertion criteria provided	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	May 07, 2019	The c.5819del variation creates a frame shift starting at codon Pro1940. The new reading frame ends in a STOP codon at position 91. This variant was detected in seven members of single family affected with Chronic Intestinal Pseudoobstructionwith (CIPO). Three unaffected members of this family did not carry the variant. -

MYH11-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 14, 2022

The MYH11 c.5819delC variant is predicted to result in a frameshift and premature protein termination (p.Pro1940Hisfs*91). This variant occurs near the c-terminus and the frameshift causes an extension of the coding region beyond the native stop codon. In an alternate transcript (NM_022844.2), this variant is known as c.5798delC (p.Pro1933Hisfs*91) and has been reported in patients with Marfan syndrome (S1 Table Gentilini et al. 2019. PubMed ID: 31536524). This variant was also found to segregate in a dominant manner in seven family members with chronic intestinal pseudo-obstruction (CIPO) (Family RQ6654 in Dong et al. 2019. PubMed ID: 31389005). In addition, this variant was found in a patient from a second family with several members with gastrointestinal dysmotility issues; however, genetic testing was preformed only on the proband (Family 2, Gilbert et al. 2020. PubMed ID: 31944481). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD; however, this variant failed to pass quality metrics in gnomAD and allele frequencies may be unreliable (http://gnomad.broadinstitute.org/variant/16-15802686-TG-T). Of note, a second variant impacting the same genetic locus (p.Gln1941Asnfs*91), and also leading to an extension of the coding sequence, was found to segregate in another family with gastrointestinal motility disorder (Family 1, Gilbert et al. 2020. PubMed ID: 31944481). Based on this evidence, we interpret the c.5819delC (p.Pro1940Hisfs*91) variant as likely pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2022

Identified by exome sequencing in a proband and multiple affected family members with chronic intestinal pseudo-obstruction in published literature and not observed in 3 unaffected relatives; reported in primary transcript of MYH11 (Dong et al., 2019); Normal stop codon changed to a Histidine codon, leading to the last 6 amino acids being replaced by 90 incorrect amino acids at the C-terminus; This variant is associated with the following publications: (PMID: 18796164, 18391202, 31536524, 31389005, 31944481, 33144682) -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs747392139; hg19: chr16-15802686;