rs112377790

Positions:

• chr16-15724368-G-A
• chr16-15724368-G-C

Variant summary

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

The NM_002474.3(MYH11):​c.4158C>T​(p.Thr1386=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,614,090 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (7 hom., cov: 32)
  • Exomes 𝑓: 0.011 (124 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.582

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=-0.65).
• BP6: Variant 16-15724368-G-A is Benign according to our data. Variant chr16-15724368-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724368-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.582 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00797 (1214/152244) while in subpopulation NFE AF= 0.0123 (839/68006). AF 95% confidence interval is 0.0116. There are 7 homozygotes in gnomad4. There are 545 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.4158C>T	p.Thr1386=	synonymous_variant	31/41	ENST00000300036.6
MYH11	NM_001040113.2	c.4179C>T	p.Thr1393=	synonymous_variant	32/43	ENST00000452625.7
NDE1	NM_017668.3	c.*117G>A		3_prime_UTR_variant	9/9	ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.4158C>T	p.Thr1386=	synonymous_variant	31/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.4179C>T	p.Thr1393=	synonymous_variant	32/43	1	NM_001040113.2
NDE1	ENST00000396354.6	c.*117G>A		3_prime_UTR_variant	9/9	1	NM_017668.3	P1

Frequencies

GnomAD3 genomes AF: 0.00798 AC: 1214 AN: 152126 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00857

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.00884 AC: 2220 AN: 251118 Hom.: 19 AF XY: 0.00900 AC XY: 1222 AN XY: 135768

Gnomad AFR exome AF: 0.00204

Gnomad AMR exome AF: 0.00720

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.00957

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0113 AC: 16476 AN: 1461846 Hom.: 124 Cov.: 72 AF XY: 0.0110 AC XY: 8000 AN XY: 727228

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.00816

Gnomad4 ASJ exome AF: 0.0141

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.00250

Gnomad4 FIN exome AF: 0.00934

Gnomad4 NFE exome AF: 0.0129

Gnomad4 OTH exome AF: 0.00982

GnomAD4 genome AF: 0.00797 AC: 1214 AN: 152244 Hom.: 7 Cov.: 32 AF XY: 0.00732 AC XY: 545 AN XY: 74442

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00857

Gnomad4 NFE AF: 0.0123

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00800 Hom.: 3

Bravo AF: 0.00789

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0127

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

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	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -
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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 16, 2016	- -
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 -

Aortic aneurysm, familial thoracic 4 Benign:4

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
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	GeneDx	Jul 23, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 20, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MYH11: BP4, BP7, BS1, BS2; NDE1: BS1, BS2 -

Lissencephaly 4 Benign:1

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. -

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	-0.65
CADD	Benign	3.0
DANN	Benign	0.82

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: rs112377790; hg19: chr16-15818225;