16-15715260-C-T

Position:

• chr16-15715260-C-T

Variant summary

Our verdict is Benign. Variant got -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 (★★).

• 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:13
• Conservation: PhyloP100: -2.31

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]

MYH11 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 138356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15715260-C-T is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.5517G>A	p.Ala1839Ala	synonymous_variant	39/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.5538G>A	p.Ala1846Ala	synonymous_variant	40/43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.948-8931C>T		intron_variant		ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.5517G>A	p.Ala1839Ala	synonymous_variant	39/41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.5538G>A	p.Ala1846Ala	synonymous_variant	40/43	1	NM_001040113.2	ENSP00000407821.2
NDE1	ENST00000396354.6	c.948-8931C>T		intron_variant		1	NM_017668.3	ENSP00000379642.1

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

GnomAD3 exomes AF: 0.0348 AC: 8733 AN: 251250 Hom.: 518 AF XY: 0.0314 AC XY: 4264 AN XY: 135806

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 SAS exome AF: 0.0262

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

Gnomad4 AFR exome AF: 0.235

Gnomad4 AMR exome AF: 0.0235

Gnomad4 ASJ exome AF: 0.0295

Gnomad4 EAS exome AF: 0.0344

Gnomad4 SAS exome AF: 0.0272

Gnomad4 FIN exome AF: 0.0293

Gnomad4 NFE exome AF: 0.0151

Gnomad4 OTH exome AF: 0.0341

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

Gnomad4 AFR AF: 0.228

Gnomad4 AMR AF: 0.0365

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.0345

Gnomad4 SAS AF: 0.0191

Gnomad4 FIN AF: 0.0333

Gnomad4 NFE AF: 0.0154

Gnomad4 OTH AF: 0.0577

Alfa AF: 0.0337 Hom.: 236

Bravo AF: 0.0846

Asia WGS AF: 0.0380 AC: 131 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:4

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 17, 2015	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Ala1846Ala in exon 40 of MYH11: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 21.4% (942/4394) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs28505375). -

Aortic aneurysm, familial thoracic 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Lissencephaly 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2014

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.12
DANN	Benign	0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs28505375; hg19: chr16-15809117; COSMIC: COSV55546756; COSMIC: COSV55546756;