NM_002474.3:c.5439G>A

Variant names:

• chr16-15717205-C-T
• rs1050162
• NM_002474.3:c.5439G>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.5439G>A​(p.Lys1813Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 1,613,910 control chromosomes in the GnomAD database, including 192,183 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 (15796 hom., cov: 33)
  • Exomes 𝑓: 0.49 (176387 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 2.30
• 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: 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 16-15717205-C-T is Benign according to our data. Variant chr16-15717205-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.514 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_002474.3	MANE Select	c.5439G>A	p.Lys1813Lys	synonymous	Exon 38 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.5460G>A	p.Lys1820Lys	synonymous	Exon 39 of 43	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.948-6986C>T		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.5439G>A	p.Lys1813Lys	synonymous	Exon 38 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.5460G>A	p.Lys1820Lys	synonymous	Exon 39 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.5460G>A	p.Lys1820Lys	synonymous	Exon 39 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67458 AN: 151992 Hom.: 15791 Cov.: 33

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.460

GnomAD2 exomes AF: 0.485 AC: 121949 AN: 251280 AF XY: 0.488

Gnomad AFR exome AF: 0.291

Gnomad AMR exome AF: 0.566

Gnomad ASJ exome AF: 0.561

Gnomad EAS exome AF: 0.307

Gnomad FIN exome AF: 0.520

Gnomad NFE exome AF: 0.506

Gnomad OTH exome AF: 0.514

GnomAD4 exome AF: 0.488 AC: 713451 AN: 1461800 Hom.: 176387 Cov.: 73 AF XY: 0.488 AC XY: 354831 AN XY: 727204

African (AFR) AF: 0.295 AC: 9890 AN: 33480

American (AMR) AF: 0.563 AC: 25195 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 14652 AN: 26136

East Asian (EAS) AF: 0.320 AC: 12690 AN: 39700

South Asian (SAS) AF: 0.471 AC: 40609 AN: 86252

European-Finnish (FIN) AF: 0.527 AC: 28139 AN: 53384

Middle Eastern (MID) AF: 0.592 AC: 3413 AN: 5768

European-Non Finnish (NFE) AF: 0.495 AC: 550138 AN: 1111962

Other (OTH) AF: 0.476 AC: 28725 AN: 60394

GnomAD4 genome AF: 0.444 AC: 67487 AN: 152110 Hom.: 15796 Cov.: 33 AF XY: 0.447 AC XY: 33226 AN XY: 74346

African (AFR) AF: 0.296 AC: 12290 AN: 41496

American (AMR) AF: 0.524 AC: 8004 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1979 AN: 3466

East Asian (EAS) AF: 0.317 AC: 1638 AN: 5162

South Asian (SAS) AF: 0.455 AC: 2194 AN: 4822

European-Finnish (FIN) AF: 0.533 AC: 5640 AN: 10580

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

European-Non Finnish (NFE) AF: 0.501 AC: 34075 AN: 67990

Other (OTH) AF: 0.456 AC: 963 AN: 2110

Alfa AF: 0.492 Hom.: 37541

Bravo AF: 0.438

Asia WGS AF: 0.369 AC: 1286 AN: 3478

EpiCase AF: 0.510

EpiControl AF: 0.512

ClinVar

ClinVar submissions

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	-0.33
CADD	Benign	8.6
DANN	Benign	0.86
PhyloP100		2.3
Mutation Taster		=100/0	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: rs1050162; hg19: chr16-15811062; COSMIC: COSV55543502; COSMIC: COSV55543502;