16-15708830-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_001040113.2(MYH11):c.5819C>G(p.Pro1940Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,605,916 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1940A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: MYH11 NM_001040113.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.54

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH11
• BP4: Computational evidence support a benign effect (MetaRNN=0.06208557).
• BP6: Variant 16-15708830-G-C is Benign according to our data. Variant chr16-15708830-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201042.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=1}. Variant chr16-15708830-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0002 (291/1454078) while in subpopulation MID AF= 0.000871 (5/5740). AF 95% confidence interval is 0.000586. There are 1 homozygotes in gnomad4_exome. There are 159 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_001040113.2	c.5819C>G	p.Pro1940Arg	missense_variant	42/43	ENST00000452625.7
MYH11	NM_002474.3	c.5787-4707C>G		intron_variant		ENST00000300036.6
NDE1	NM_017668.3	c.947+11970G>C		intron_variant		ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000452625.7	c.5819C>G	p.Pro1940Arg	missense_variant	42/43	1	NM_001040113.2
MYH11	ENST00000300036.6	c.5787-4707C>G		intron_variant		1	NM_002474.3	P3
NDE1	ENST00000396354.6	c.947+11970G>C		intron_variant		1	NM_017668.3	P1

Frequencies

GnomAD3 genomes AF: 0.000198 AC: 30 AN: 151720 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000407 AC: 95 AN: 233460 Hom.: 0 AF XY: 0.000365 AC XY: 46 AN XY: 126162

Gnomad AFR exome AF: 0.0000689

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000691

Gnomad SAS exome AF: 0.00117

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000315

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.000200 AC: 291 AN: 1454078 Hom.: 1 Cov.: 32 AF XY: 0.000220 AC XY: 159 AN XY: 722616

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.000411

Gnomad4 ASJ exome AF: 0.000116

Gnomad4 EAS exome AF: 0.000657

Gnomad4 SAS exome AF: 0.000732

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.000233

GnomAD4 genome AF: 0.000198 AC: 30 AN: 151838 Hom.: 0 Cov.: 33 AF XY: 0.000189 AC XY: 14 AN XY: 74236

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000295

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.000174

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000363 AC: 44

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 28, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Oct 19, 2016	- -

not provided Uncertain:1 Benign:1

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Reported using an alternate transcript of the gene; Identified in a patient with TAAD in published literature who also harbored a variant in the COL3A1 gene (Li et al., 2021); This variant is associated with the following publications: (PMID: 34498425) -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 29, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	20
Dann	Benign	0.79
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.39	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.062	T;T
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	D;D;N;N;N;D;D;D
PROVEAN	Benign	-0.86	N;.
REVEL	Benign	0.24
Sift	Uncertain	0.0070	D;.
Sift4G	Benign	0.75	T;T
Vest4		0.47
MVP		0.41
ClinPred		0.036	T
GERP RS		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs111588143; hg19: chr16-15802687;