rs587781061

Positions:

• chr16-15721478-T-C
• chrNT_187607.1-1379489-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_002474.3(MYH11):​c.4522A>G​(p.Met1508Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,614,156 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (9 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.444

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]

MYH11 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0114298165).
• BP6: Variant 16-15721478-T-C is Benign according to our data. Variant chr16-15721478-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138345.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=8}. Variant chr16-15721478-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00431 (656/152262) while in subpopulation AFR AF= 0.0134 (555/41560). AF 95% confidence interval is 0.0124. There are 1 homozygotes in gnomad4. There are 335 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.4522A>G	p.Met1508Val	missense_variant	32/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.4543A>G	p.Met1515Val	missense_variant	33/43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.948-2713T>C		intron_variant		ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.4522A>G	p.Met1508Val	missense_variant	32/41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.4543A>G	p.Met1515Val	missense_variant	33/43	1	NM_001040113.2	ENSP00000407821.2
NDE1	ENST00000396354.6	c.948-2713T>C		intron_variant		1	NM_017668.3	ENSP00000379642.1

Frequencies

GnomAD3 genomes AF: 0.00429 AC: 653 AN: 152144 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00134 AC: 338 AN: 251492 Hom.: 1 AF XY: 0.00107 AC XY: 146 AN XY: 135922

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000804 AC: 1175 AN: 1461894 Hom.: 9 Cov.: 32 AF XY: 0.000708 AC XY: 515 AN XY: 727248

Gnomad4 AFR exome AF: 0.0152

Gnomad4 AMR exome AF: 0.00212

Gnomad4 ASJ exome AF: 0.00459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000299

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00431 AC: 656 AN: 152262 Hom.: 1 Cov.: 32 AF XY: 0.00450 AC XY: 335 AN XY: 74458

Gnomad4 AFR AF: 0.0134

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00118 Hom.: 3

Bravo AF: 0.00472

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0162 AC: 71

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00143 AC: 174

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	May 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Nov 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2014	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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 07, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MYH11: BS1 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 29, 2021	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2015

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.33	.;.;.;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.89	D;D;D;D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.97	.;.;L;L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.70	N;N;.;N
REVEL	Benign	0.22
Sift	Benign	0.30	T;T;.;T
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.0040	.;.;.;B
Vest4		0.35
MVP		0.34
MPC		0.19
ClinPred		0.012	T
GERP RS		4.8
Varity_R		0.13
gMVP		0.24

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: rs35176378; hg19: chr16-15815335;