rs587781059

Positions:

• chr16-15724284-A-C
• chrNT_187607.1-1382295-A-C
• chr16-15724284-A-T
• chrNT_187607.1-1382295-A-T
• chr16-15724284-A-G
• chrNT_187607.1-1382295-A-G

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.4242T>G​(p.Ala1414=) 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 (★★).

• 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:19
• Conservation: PhyloP100: 0.512

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 -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 id is 138342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724284-A-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.4242T>G	p.Ala1414=	synonymous_variant	31/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.4263T>G	p.Ala1421=	synonymous_variant	32/43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.*33A>C		3_prime_UTR_variant	9/9	ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.4242T>G	p.Ala1414=	synonymous_variant	31/41	1	NM_002474.3	ENSP00000300036	P3
MYH11	ENST00000452625.7	c.4263T>G	p.Ala1421=	synonymous_variant	32/43	1	NM_001040113.2	ENSP00000407821
NDE1	ENST00000396354.6	c.*33A>C		3_prime_UTR_variant	9/9	1	NM_017668.3	ENSP00000379642	P1

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

GnomAD3 exomes AF: 0.506 AC: 127325 AN: 251440 Hom.: 33443 AF XY: 0.512 AC XY: 69536 AN XY: 135892

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 SAS exome AF: 0.518

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

Gnomad4 AFR exome AF: 0.298

Gnomad4 AMR exome AF: 0.584

Gnomad4 ASJ exome AF: 0.661

Gnomad4 EAS exome AF: 0.297

Gnomad4 SAS exome AF: 0.521

Gnomad4 FIN exome AF: 0.522

Gnomad4 NFE exome AF: 0.514

Gnomad4 OTH exome AF: 0.499

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

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.543

Gnomad4 ASJ AF: 0.671

Gnomad4 EAS AF: 0.300

Gnomad4 SAS AF: 0.503

Gnomad4 FIN AF: 0.529

Gnomad4 NFE AF: 0.521

Gnomad4 OTH AF: 0.497

Alfa AF: 0.518 Hom.: 32845

Bravo AF: 0.455

Asia WGS AF: 0.377 AC: 1315 AN: 3478

EpiCase AF: 0.543

EpiControl AF: 0.542

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 19, 2014	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Ala1421Ala in exon 32 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 46.4% (3990/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2075511). -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

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	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

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. -

Lissencephaly, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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	-0.55
CADD	Benign	7.2
DANN	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs2075511; hg19: chr16-15818141; COSMIC: COSV55545772; COSMIC: COSV55545772;