16-15715260-C-T

Variant names:

• chr16-15715260-C-T
• rs28505375
• NM_002474.3:c.5517G>A

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.5517G>A​(p.Ala1839Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,613,830 control chromosomes in the GnomAD database, including 2,374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1839A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.078 (1132 hom., cov: 32)
  • Exomes 𝑓: 0.023 (1242 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -2.31
• Publications: 8 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=-0.68).
• BP6: Variant 16-15715260-C-T is Benign according to our data. Variant chr16-15715260-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.224 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.5517G>A	p.Ala1839Ala	synonymous	Exon 39 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.5538G>A	p.Ala1846Ala	synonymous	Exon 40 of 43	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.948-8931C>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.5517G>A	p.Ala1839Ala	synonymous	Exon 39 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.5538G>A	p.Ala1846Ala	synonymous	Exon 40 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.5538G>A	p.Ala1846Ala	synonymous	Exon 40 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.0782 AC: 11889 AN: 151986 Hom.: 1132 Cov.: 32

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0367

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.0344

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.0333

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.0578

GnomAD2 exomes AF: 0.0348 AC: 8733 AN: 251250 AF XY: 0.0314

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.0210

Gnomad ASJ exome AF: 0.0274

Gnomad EAS exome AF: 0.0281

Gnomad FIN exome AF: 0.0321

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0290

GnomAD4 exome AF: 0.0233 AC: 34068 AN: 1461726 Hom.: 1242 Cov.: 34 AF XY: 0.0229 AC XY: 16688 AN XY: 727158

African (AFR) AF: 0.235 AC: 7881 AN: 33470

American (AMR) AF: 0.0235 AC: 1053 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0295 AC: 772 AN: 26136

East Asian (EAS) AF: 0.0344 AC: 1367 AN: 39698

South Asian (SAS) AF: 0.0272 AC: 2347 AN: 86254

European-Finnish (FIN) AF: 0.0293 AC: 1565 AN: 53348

Middle Eastern (MID) AF: 0.0377 AC: 217 AN: 5754

European-Non Finnish (NFE) AF: 0.0151 AC: 16805 AN: 1111958

Other (OTH) AF: 0.0341 AC: 2061 AN: 60384

GnomAD4 genome AF: 0.0783 AC: 11908 AN: 152104 Hom.: 1132 Cov.: 32 AF XY: 0.0776 AC XY: 5767 AN XY: 74360

African (AFR) AF: 0.228 AC: 9453 AN: 41458

American (AMR) AF: 0.0365 AC: 557 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3472

East Asian (EAS) AF: 0.0345 AC: 178 AN: 5164

South Asian (SAS) AF: 0.0191 AC: 92 AN: 4824

European-Finnish (FIN) AF: 0.0333 AC: 353 AN: 10594

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0154 AC: 1047 AN: 68002

Other (OTH) AF: 0.0577 AC: 122 AN: 2114

Alfa AF: 0.0352 Hom.: 262

Bravo AF: 0.0846

Asia WGS AF: 0.0380 AC: 131 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.12
DANN	Benign	0.88
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: rs28505375; hg19: chr16-15809117; COSMIC: COSV55546756; COSMIC: COSV55546756;