rs2075511

Variant names:

• chr16-15724284-A-C
• rs2075511
• NM_002474.3:c.4242T>G

Your query was ambiguous. Multiple possible variants found:

• chr16-15724284-A-C
• chr16-15724284-A-G
• chr16-15724284-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002474.3(MYH11):​c.4242T>G​(p.Ala1414Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 1,613,830 control chromosomes in the GnomAD database, including 209,113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1414A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.46 (17018 hom., cov: 32)
  • Exomes 𝑓: 0.51 (192095 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.512
• Publications: 37 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 16-15724284-A-C is Benign according to our data. Variant chr16-15724284-A-C is described in ClinVar as Benign. ClinVar VariationId is 138342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.512 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.533 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.4242T>G	p.Ala1414Ala	synonymous	Exon 31 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.4263T>G	p.Ala1421Ala	synonymous	Exon 32 of 43	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.*33A>C		3_prime_UTR	Exon 9 of 9	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.4242T>G	p.Ala1414Ala	synonymous	Exon 31 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.4263T>G	p.Ala1421Ala	synonymous	Exon 32 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.4263T>G	p.Ala1421Ala	synonymous	Exon 32 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69802 AN: 151852 Hom.: 17015 Cov.: 32

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.600

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.503

Gnomad FIN AF: 0.529

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.501

GnomAD2 exomes AF: 0.506 AC: 127325 AN: 251440 AF XY: 0.512

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.586

Gnomad ASJ exome AF: 0.659

Gnomad EAS exome AF: 0.287

Gnomad FIN exome AF: 0.518

Gnomad NFE exome AF: 0.527

Gnomad OTH exome AF: 0.545

GnomAD4 exome AF: 0.509 AC: 743663 AN: 1461860 Hom.: 192095 Cov.: 90 AF XY: 0.510 AC XY: 371156 AN XY: 727224

African (AFR) AF: 0.298 AC: 9979 AN: 33480

American (AMR) AF: 0.584 AC: 26124 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 17288 AN: 26136

East Asian (EAS) AF: 0.297 AC: 11777 AN: 39700

South Asian (SAS) AF: 0.521 AC: 44934 AN: 86248

European-Finnish (FIN) AF: 0.522 AC: 27859 AN: 53414

Middle Eastern (MID) AF: 0.642 AC: 3690 AN: 5752

European-Non Finnish (NFE) AF: 0.514 AC: 571847 AN: 1112010

Other (OTH) AF: 0.499 AC: 30165 AN: 60396

GnomAD4 genome AF: 0.459 AC: 69827 AN: 151970 Hom.: 17018 Cov.: 32 AF XY: 0.462 AC XY: 34348 AN XY: 74272

African (AFR) AF: 0.301 AC: 12475 AN: 41446

American (AMR) AF: 0.543 AC: 8294 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 2326 AN: 3468

East Asian (EAS) AF: 0.300 AC: 1552 AN: 5174

South Asian (SAS) AF: 0.503 AC: 2421 AN: 4814

European-Finnish (FIN) AF: 0.529 AC: 5586 AN: 10550

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.521 AC: 35399 AN: 67928

Other (OTH) AF: 0.497 AC: 1052 AN: 2116

Alfa AF: 0.514 Hom.: 39564

Bravo AF: 0.455

Asia WGS AF: 0.377 AC: 1315 AN: 3478

EpiCase AF: 0.543

EpiControl AF: 0.542

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Aortic aneurysm, familial thoracic 4 (5)
-	-	4	not specified (4)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Lissencephaly 4 (1)
-	-	1	Lissencephaly, Recessive (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	-0.55
CADD	Benign	7.2
DANN	Benign	0.72
PhyloP100		0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2075511; hg19: chr16-15818141; COSMIC: COSV55545772; COSMIC: COSV55545772;