rs137934837

Positions:

• chr16-15721026-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 2P and 18B. PP2 PP3 BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_002474.3(MYH11):​c.4604G>A​(p.Arg1535Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,614,018 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (7 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:12
• Conservation: PhyloP100: 7.91

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 -16 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH11. . Gene score misZ 1.4389 (greater than the threshold 3.09). Trascript score misZ 3.4142 (greater than threshold 3.09). GenCC has associacion of gene with aortic aneurysm, familial thoracic 4, visceral myopathy 2, familial thoracic aortic aneurysm and aortic dissection, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, megacystis-microcolon-intestinal hypoperistalsis syndrome.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, Cadd, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.103137344).
• BP6: Variant 16-15721026-C-T is Benign according to our data. Variant chr16-15721026-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 180418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15721026-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00217 (330/152186) while in subpopulation NFE AF= 0.00325 (221/68006). AF 95% confidence interval is 0.0029. There are 0 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.4604G>A	p.Arg1535Gln	missense_variant	33/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.4625G>A	p.Arg1542Gln	missense_variant	34/43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.948-3165C>T		intron_variant		ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.4604G>A	p.Arg1535Gln	missense_variant	33/41	1	NM_002474.3	ENSP00000300036	P3
MYH11	ENST00000452625.7	c.4625G>A	p.Arg1542Gln	missense_variant	34/43	1	NM_001040113.2	ENSP00000407821
NDE1	ENST00000396354.6	c.948-3165C>T		intron_variant		1	NM_017668.3	ENSP00000379642	P1

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 331 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000967

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00222 AC: 559 AN: 251412 Hom.: 1 AF XY: 0.00232 AC XY: 315 AN XY: 135892

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00125

Gnomad SAS exome AF: 0.00199

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00312

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00315 AC: 4603 AN: 1461832 Hom.: 7 Cov.: 32 AF XY: 0.00309 AC XY: 2245 AN XY: 727228

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.00310

Gnomad4 EAS exome AF: 0.00116

Gnomad4 SAS exome AF: 0.00198

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00352

Gnomad4 OTH exome AF: 0.00366

GnomAD4 genome AF: 0.00217 AC: 330 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74418

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000969

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00325

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00335 Hom.: 2

Bravo AF: 0.00243

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00234 AC: 284

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2 Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Blueprint Genetics	May 19, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 13, 2018	This alteration is classified as likely 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. -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 29, 2019	- -

Aortic aneurysm, familial thoracic 4 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 11, 2019	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Sep 26, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MYH11: BS1, BS2 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Mar 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2018	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. -

MYH11-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	.;.;.;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.7	.;.;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.2	D;D;.;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.023	D;D;.;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.79
MVP		0.85
MPC		0.77
ClinPred		0.096	T
GERP RS		5.0
Varity_R		0.50
gMVP		0.46

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: rs137934837; hg19: chr16-15814883; COSMIC: COSV100257453; COSMIC: COSV100257453;