rs1050163

Variant names:

• chr16-15717166-C-T
• rs1050163
• NM_002474.3:c.5478G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002474.3(MYH11):​c.5478G>A​(p.Leu1826Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 1,613,846 control chromosomes in the GnomAD database, including 191,592 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15757 hom., cov: 33)
  • Exomes 𝑓: 0.49 (175835 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 1.43
• Publications: 22 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: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 16-15717166-C-T is Benign according to our data. Variant chr16-15717166-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_002474.3	MANE Select	c.5478G>A	p.Leu1826Leu	synonymous	Exon 38 of 41	NP_002465.1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.5499G>A	p.Leu1833Leu	synonymous	Exon 39 of 43	NP_001035202.1
	NDE1	NM_017668.3	MANE Select	c.948-7025C>T		intron	N/A	NP_060138.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.5478G>A	p.Leu1826Leu	synonymous	Exon 38 of 41	ENSP00000300036.5
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.5499G>A	p.Leu1833Leu	synonymous	Exon 39 of 43	ENSP00000407821.2
	MYH11	ENST00000396324.7	TSL:1	c.5499G>A	p.Leu1833Leu	synonymous	Exon 39 of 42	ENSP00000379616.3

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67411 AN: 151968 Hom.: 15752 Cov.: 33

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.588

Gnomad AMR AF: 0.522

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.459

GnomAD2 exomes AF: 0.485 AC: 121786 AN: 251204 AF XY: 0.487

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.566

Gnomad ASJ exome AF: 0.561

Gnomad EAS exome AF: 0.306

Gnomad FIN exome AF: 0.520

Gnomad NFE exome AF: 0.505

Gnomad OTH exome AF: 0.514

GnomAD4 exome AF: 0.487 AC: 712259 AN: 1461760 Hom.: 175835 Cov.: 67 AF XY: 0.487 AC XY: 354228 AN XY: 727192

African (AFR) AF: 0.297 AC: 9940 AN: 33478

American (AMR) AF: 0.563 AC: 25189 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 14647 AN: 26134

East Asian (EAS) AF: 0.319 AC: 12682 AN: 39700

South Asian (SAS) AF: 0.470 AC: 40574 AN: 86256

European-Finnish (FIN) AF: 0.527 AC: 28120 AN: 53400

Middle Eastern (MID) AF: 0.591 AC: 3411 AN: 5768

European-Non Finnish (NFE) AF: 0.494 AC: 549022 AN: 1111910

Other (OTH) AF: 0.475 AC: 28674 AN: 60390

GnomAD4 genome AF: 0.443 AC: 67441 AN: 152086 Hom.: 15757 Cov.: 33 AF XY: 0.447 AC XY: 33206 AN XY: 74354

African (AFR) AF: 0.298 AC: 12352 AN: 41504

American (AMR) AF: 0.522 AC: 7971 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1980 AN: 3466

East Asian (EAS) AF: 0.317 AC: 1637 AN: 5158

South Asian (SAS) AF: 0.455 AC: 2198 AN: 4826

European-Finnish (FIN) AF: 0.533 AC: 5629 AN: 10566

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.500 AC: 34011 AN: 67976

Other (OTH) AF: 0.455 AC: 961 AN: 2112

Alfa AF: 0.490 Hom.: 42102

Bravo AF: 0.438

Asia WGS AF: 0.370 AC: 1287 AN: 3478

EpiCase AF: 0.510

EpiControl AF: 0.511

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Aortic aneurysm, familial thoracic 4 (6)
-	-	6	not specified (6)
-	-	4	Familial thoracic aortic aneurysm and aortic dissection (4)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Lissencephaly 4 (1)
-	-	1	Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 (1)
-	-	1	Visceral myopathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.6
DANN	Benign	0.89
PhyloP100		1.4
Mutation Taster		=99/1	polymorphism (auto)

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: rs1050163; hg19: chr16-15811023; COSMIC: COSV55543481; COSMIC: COSV55543481;