rs587781053

Positions:

• chr16-15726878-C-T
• chrNT_187607.1-1384889-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000300036.6(MYH11):​c.3828G>A​(p.Ala1276=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,612,150 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0037 (22 hom.)
• Consequence: MYH11 ENST00000300036.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -4.49

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]

(HGNC:):

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=-0.74).
• BP6: Variant 16-15726878-C-T is Benign according to our data. Variant chr16-15726878-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 138335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15726878-C-T is described in Lovd as [Likely_benign]. Variant chr16-15726878-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00244 (372/152160) while in subpopulation NFE AF= 0.00413 (281/68006). AF 95% confidence interval is 0.00373. There are 3 homozygotes in gnomad4. There are 159 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.3828G>A	p.Ala1276=	synonymous_variant	28/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.3849G>A	p.Ala1283=	synonymous_variant	29/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.3849G>A	p.Ala1283=	synonymous_variant	29/42		NP_001035203.1
MYH11	NM_022844.3	c.3828G>A	p.Ala1276=	synonymous_variant	28/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.3828G>A	p.Ala1276=	synonymous_variant	28/41	1	NM_002474.3	ENSP00000300036	P3
MYH11	ENST00000452625.7	c.3849G>A	p.Ala1283=	synonymous_variant	29/43	1	NM_001040113.2	ENSP00000407821
	ENST00000574212.1	n.205C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00245 AC: 372 AN: 152042 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00413

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00281 AC: 702 AN: 249838 Hom.: 3 AF XY: 0.00309 AC XY: 418 AN XY: 135242

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.000343

Gnomad NFE exome AF: 0.00432

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00371 AC: 5415 AN: 1459990 Hom.: 22 Cov.: 30 AF XY: 0.00368 AC XY: 2670 AN XY: 726404

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.00212

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00252

Gnomad4 FIN exome AF: 0.000175

Gnomad4 NFE exome AF: 0.00432

Gnomad4 OTH exome AF: 0.00291

GnomAD4 genome AF: 0.00244 AC: 372 AN: 152160 Hom.: 3 Cov.: 31 AF XY: 0.00214 AC XY: 159 AN XY: 74380

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000755

Gnomad4 NFE AF: 0.00413

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00334 Hom.: 0

Bravo AF: 0.00265

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00575

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 08, 2016	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 19, 2014	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 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	Eurofins Ntd Llc (ga)	Jan 22, 2018	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MYH11: BP4, BP7, BS2 -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2015

This alteration is classified as likely 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. -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.18
DANN	Benign	0.85

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: rs113154524; hg19: chr16-15820735; COSMIC: COSV55551730; COSMIC: COSV55551730;