rs587781066

chr16-15717205-C-TchrNT_187607.1-1375215-C-Tchr16-15717205-C-GchrNT_187607.1-1375215-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002474.3(MYH11):c.5439G>A(p.Lys1813=) 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:20
• Conservation: PhyloP100: 2.30

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 138353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15717205-C-T is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.5439G>A	p.Lys1813=	synonymous_variant	38/41	ENST00000300036.6
MYH11	NM_001040113.2	c.5460G>A	p.Lys1820=	synonymous_variant	39/43	ENST00000452625.7
NDE1	NM_017668.3	c.948-6986C>T		intron_variant		ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.5439G>A	p.Lys1813=	synonymous_variant	38/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.5460G>A	p.Lys1820=	synonymous_variant	39/43	1	NM_001040113.2
NDE1	ENST00000396354.6	c.948-6986C>T		intron_variant		1	NM_017668.3	P1

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

GnomAD3 exomes AF: 0.485 AC: 121949 AN: 251280 Hom.: 30508 AF XY: 0.488 AC XY: 66288 AN XY: 135840

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 SAS exome AF: 0.471

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

Gnomad4 AFR exome AF: 0.295

Gnomad4 AMR exome AF: 0.563

Gnomad4 ASJ exome AF: 0.561

Gnomad4 EAS exome AF: 0.320

Gnomad4 SAS exome AF: 0.471

Gnomad4 FIN exome AF: 0.527

Gnomad4 NFE exome AF: 0.495

Gnomad4 OTH exome AF: 0.476

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

Gnomad4 AFR AF: 0.296

Gnomad4 AMR AF: 0.524

Gnomad4 ASJ AF: 0.571

Gnomad4 EAS AF: 0.317

Gnomad4 SAS AF: 0.455

Gnomad4 FIN AF: 0.533

Gnomad4 NFE AF: 0.501

Gnomad4 OTH AF: 0.456

Alfa AF: 0.497 Hom.: 31515

Bravo AF: 0.438

Asia WGS AF: 0.369 AC: 1286 AN: 3478

EpiCase AF: 0.510

EpiControl AF: 0.512

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Benign:6

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2012	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	Lys1820Lys in exon 39 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 49.2% (4229/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1050162). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 19, 2015	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Visceral myopathy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 30, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 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	-0.33
Cadd	Benign	8.6
Dann	Benign	0.86

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: rs1050162; hg19: chr16-15811062; COSMIC: COSV55543502; COSMIC: COSV55543502;