16-15708830-G-T

Position:

• chr16-15708830-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001040113.2(MYH11):​c.5819C>A​(p.Pro1940Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,605,908 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1940L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (0 hom.)
• Consequence: MYH11 NM_001040113.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:12
• 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]

MYH11 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 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 3.3894 (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=0.0077909827).
• BP6: Variant 16-15708830-G-T is Benign according to our data. Variant chr16-15708830-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 201041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15708830-G-T is described in Lovd as [Likely_benign]. Variant chr16-15708830-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00331 (503/151838) while in subpopulation AFR AF= 0.00891 (369/41422). AF 95% confidence interval is 0.00816. There are 4 homozygotes in gnomad4. There are 243 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_001040113.2	c.5819C>A	p.Pro1940Gln	missense_variant	42/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_002474.3	c.5787-4707C>A		intron_variant		ENST00000300036.6	NP_002465.1
NDE1	NM_017668.3	c.947+11970G>T		intron_variant		ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000452625.7	c.5819C>A	p.Pro1940Gln	missense_variant	42/43	1	NM_001040113.2	ENSP00000407821.2
MYH11	ENST00000300036.6	c.5787-4707C>A		intron_variant		1	NM_002474.3	ENSP00000300036.5
NDE1	ENST00000396354.6	c.947+11970G>T		intron_variant		1	NM_017668.3	ENSP00000379642.1

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 501 AN: 151720 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00889

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00211

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00124

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00133 AC: 311 AN: 233460 Hom.: 1 AF XY: 0.00117 AC XY: 148 AN XY: 126162

Gnomad AFR exome AF: 0.00876

Gnomad AMR exome AF: 0.000771

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.000691

Gnomad SAS exome AF: 0.000212

Gnomad FIN exome AF: 0.000290

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00190

GnomAD4 exome AF: 0.00147 AC: 2132 AN: 1454070 Hom.: 0 Cov.: 32 AF XY: 0.00141 AC XY: 1021 AN XY: 722608

Gnomad4 AFR exome AF: 0.00788

Gnomad4 AMR exome AF: 0.000891

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.000961

Gnomad4 SAS exome AF: 0.000260

Gnomad4 FIN exome AF: 0.000415

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00331 AC: 503 AN: 151838 Hom.: 4 Cov.: 33 AF XY: 0.00327 AC XY: 243 AN XY: 74236

Gnomad4 AFR AF: 0.00891

Gnomad4 AMR AF: 0.00210

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00124

Gnomad4 OTH AF: 0.00238

Alfa AF: 0.000193 Hom.: 0

Bravo AF: 0.00340

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00774 AC: 34

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00138 AC: 167

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	MYH11: BP4, BS2; NDE1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2015	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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 11, 2018	Variant summary: MYH11 c.5819C>A (p.Pro1940Gln) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 259712 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 1229-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. Yeung_2017 reports the variant in one patient with aortic aneurysm (AA) and following an evaluation of the effect of the variant on RNA splicing concluded that transcripts containing exon 42 are not expressed in smooth muscle cell (SMC)-like cells or primary SMC and therefore, the variant c.5819C>A in MYH11 is not pathogenic and variants in exon 42 are not relevant for familial thoracic AA. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 10, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Benign	0.96
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.28	T;T
MetaRNN	Benign	0.0078	T;T
MetaSVM	Benign	-0.58	T
PROVEAN	Benign	-0.95	N;.
REVEL	Benign	0.22
Sift	Uncertain	0.0080	D;.
Sift4G	Benign	0.43	T;T
Vest4		0.39
MVP		0.43
ClinPred		0.041	T
GERP RS		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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; COSMIC: COSV100257523; COSMIC: COSV100257523;