rs111858392

Variant names:

• chr16-15717358-A-G
• rs111858392
• NM_002474.3:c.5296-10T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_002474.3(MYH11):​c.5296-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000823 in 1,603,988 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (1 hom.)
• Consequence: MYH11 NM_002474.3 intron
• Scores: Splicing: ADA: 0.00002659
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.0180
• Publications: 0 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 16-15717358-A-G is Benign according to our data. Variant chr16-15717358-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 318098.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000368 (56/152056) while in subpopulation AFR AF = 0.00133 (55/41468). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002474.3. 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_002474.3	MANE Select	c.5296-10T>C		intron	N/A	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.5317-10T>C		intron	N/A	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.948-6833A>G		intron	N/A	NP_060138.1	Q9NXR1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.5296-10T>C		intron	N/A	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.5317-10T>C		intron	N/A	ENSP00000407821.2	P35749-3
	NDE1	ENST00000396354.6	TSL:1 MANE Select	c.948-6833A>G		intron	N/A	ENSP00000379642.1	Q9NXR1-2

Frequencies

GnomAD3 genomes AF: 0.000336 AC: 51 AN: 151940 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000742 AC: 18 AN: 242472 AF XY: 0.0000759

Gnomad AFR exome AF: 0.000874

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000523 AC: 76 AN: 1451932 Hom.: 1 Cov.: 33 AF XY: 0.0000554 AC XY: 40 AN XY: 722660

African (AFR) AF: 0.00122 AC: 41 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43732

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111852

Other (OTH) AF: 0.000448 AC: 27 AN: 60322

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152056 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74322

African (AFR) AF: 0.00133 AC: 55 AN: 41468

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000340

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Aortic aneurysm, familial thoracic 4 (2)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	1	-	Lissencephaly, Recessive (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.3
DANN	Benign	0.75
PhyloP100		-0.018
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.050
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: rs111858392; hg19: chr16-15811215;