16-15720860-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_002474.3(MYH11):c.4770G>A(p.Lys1590Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,613,842 control chromosomes in the GnomAD database, including 357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 23 hom., cov: 31)

Exomes 𝑓: 0.018 ( 334 hom. )

Consequence

MYH11
NM_002474.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 2.80

Variant links:

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]

MYH11 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 16-15720860-C-T is Benign according to our data. Variant chr16-15720860-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 36621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15720860-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=2.8 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.013 (1974/152260) while in subpopulation NFE AF= 0.0211 (1433/68018). AF 95% confidence interval is 0.0202. There are 23 homozygotes in gnomad4. There are 897 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3 link	c.4770G>A	p.Lys1590Lys	synonymous_variant	Exon 33 of 41	ENST00000300036.6	NP_002465.1	P35749-1A0A024QZJ4
MYH11	NM_001040113.2 link	c.4791G>A	p.Lys1597Lys	synonymous_variant	Exon 34 of 43	ENST00000452625.7	NP_001035202.1	P35749-3
NDE1	NM_017668.3 link	c.948-3331C>T		intron_variant	Intron 8 of 8	ENST00000396354.6	NP_060138.1	Q9NXR1-2X5DR54

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH11	ENST00000300036.6 link	c.4770G>A	p.Lys1590Lys	synonymous_variant	Exon 33 of 41	1	NM_002474.3	ENSP00000300036.5	P35749-1
MYH11	ENST00000452625.7 link	c.4791G>A	p.Lys1597Lys	synonymous_variant	Exon 34 of 43	1	NM_001040113.2	ENSP00000407821.2	P35749-3
NDE1	ENST00000396354.6 link	c.948-3331C>T		intron_variant	Intron 8 of 8	1	NM_017668.3	ENSP00000379642.1	Q9NXR1-2

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1975

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00410

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00550

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0225

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0211

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.0136

AC:

3424

AN:

251274

Hom.:

AF XY:

0.0137

AC XY:

1862

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.00411

Gnomad ASJ exome

AF:

0.00556

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00421

Gnomad FIN exome

AF:

0.0272

Gnomad NFE exome

AF:

0.0208

Gnomad OTH exome

AF:

0.0134

GnomAD4 exome

AF:

0.0184

AC:

26867

AN:

1461582

Hom.:

334

Cov.:

AF XY:

0.0179

AC XY:

13025

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.00281

Gnomad4 AMR exome

AF:

0.00425

Gnomad4 ASJ exome

AF:

0.00605

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00475

Gnomad4 FIN exome

AF:

0.0276

Gnomad4 NFE exome

AF:

0.0214

Gnomad4 OTH exome

AF:

0.0128

GnomAD4 genome

AF:

0.0130

AC:

1974

AN:

152260

Hom.:

Cov.:

AF XY:

0.0120

AC XY:

897

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00409

Gnomad4 AMR

AF:

0.00543

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.0225

Gnomad4 NFE

AF:

0.0211

Gnomad4 OTH

AF:

0.00805

Alfa

AF:

0.0174

Hom.:

Bravo

AF:

0.0109

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0183

EpiControl

AF:

0.0168

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 05, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lys1597Lys in exon 34 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 2.1% (177/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs11648119). -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:4

Mar 07, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 09, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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. -

Aortic aneurysm, familial thoracic 4

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Benign:2

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial aortopathy

Benign:1

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Lissencephaly 4

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.1

DANN

Benign

0.69

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over