16-15708829-TGGG-TGG

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Moderate 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).

• 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: 12 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: Uncertain_significance. The variant received 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 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;