chr16-15708829-TG-T

Variant names:

• chr16-15708829-TG-T
• rs747392139
• NM_001040113.2:c.5819delC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Moderate PS3 PP5

The NM_001040113.2(MYH11):​c.5819delC​(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). ClinVar reports functional evidence for this variant: "SCV005399931: "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)."".

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MYH11 NM_001040113.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2
• Conservation: PhyloP100: 1.54
• Publications: 13 publications found

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]

NDE1 Gene-Disease associations (from GenCC):

• lissencephaly 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Ambry Genetics
• microcephaly with lissencephaly and/or hydranencephaly

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hydranencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• microlissencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• NDE1-related microhydranencephaly

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005399931: "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)."
• 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 VariationId is 627645.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040113.2. 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
	MYH11	NM_001040113.2	MANE Plus Clinical	c.5819delC	p.Pro1940HisfsTer91	frameshift	Exon 42 of 43	NP_001035202.1	P35749-3
	MYH11	NM_002474.3	MANE Select	c.5787-4707delC		intron	N/A	NP_002465.1	P35749-1
	NDE1	NM_017668.3	MANE Select	c.947+11977delG		intron	N/A	NP_060138.1	Q9NXR1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.5819delC	p.Pro1940HisfsTer91	frameshift	Exon 42 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000576790.7	TSL:1	c.5798delC	p.Pro1933HisfsTer13	frameshift	Exon 41 of 42	ENSP00000458731.1	P35749-4
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.5787-4707delC		intron	N/A	ENSP00000300036.5	P35749-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000682 AC: 16 AN: 234464 AF XY: 0.0000710

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000923

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.000114

Gnomad FIN exome AF: 0.0000483

Gnomad NFE exome AF: 0.0000569

Gnomad OTH exome AF: 0.00

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.0000683 AC: 3 AN: 43950

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25928

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.0000354 AC: 3 AN: 84800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000632 AC: 7 AN: 1107376

Other (OTH) AF: 0.00 AC: 0 AN: 60126

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000002534), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	-	Visceral myopathy 2 (3)
2	-	-	Chronic intestinal pseudoobstruction (2)
-	1	-	Aortic aneurysm, familial thoracic 4 (1)
1	-	-	MYH11-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=2/198	disease causing

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: rs747392139; hg19: chr16-15802686; COSMIC: COSV55541776; COSMIC: COSV55541776;