chr16-15724977-C-G

Position:

• chr16-15724977-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BP6

The NM_002474.3(MYH11):​c.3874G>C​(p.Val1292Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• 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]

MYH11 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 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=0.20446149).
• BP6: Variant 16-15724977-C-G is Benign according to our data. Variant chr16-15724977-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 534147.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.3874G>C	p.Val1292Leu	missense_variant	29/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.3895G>C	p.Val1299Leu	missense_variant	30/43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.*726C>G		3_prime_UTR_variant	9/9	ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.3874G>C	p.Val1292Leu	missense_variant	29/41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.3895G>C	p.Val1299Leu	missense_variant	30/43	1	NM_001040113.2	ENSP00000407821.2
NDE1	ENST00000396354.6	c.*726C>G		3_prime_UTR_variant	9/9	1	NM_017668.3	ENSP00000379642.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000478 AC: 12 AN: 251272 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135840

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461768 Hom.: 0 Cov.: 34 AF XY: 0.0000206 AC XY: 15 AN XY: 727196

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74432

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Bravo AF: 0.000200

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 05, 2024	The p.V1292L variant (also known as c.3874G>C), located in coding exon 28 of the MYH11 gene, results from a G to C substitution at nucleotide position 3874. The valine at codon 1292 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 20, 2020	- -

Aortic aneurysm, familial thoracic 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 29, 2023

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1299 of the MYH11 protein (p.Val1299Leu). This variant is present in population databases (rs151058774, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 534147). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH11 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2022

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 06, 2021

Variant summary: MYH11 c.3895G>C (p.Val1299Leu) results in a conservative amino acid change located in the Myosin tail domain of 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 4.8e-05 in 251272 control chromosomes. The observed variant frequency is approximately 3.82 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Thoracic Aortic Aneurysms And Dissections phenotype (1.3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3895G>C in individuals affected with Thoracic Aortic Aneurysms And Dissections and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.43	.;.;.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.074
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.64	.;.;N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.4	N;N;.;N
REVEL	Benign	0.20
Sift	Benign	0.66	T;T;.;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.050	.;.;.;B
Vest4		0.69
MVP		0.76
MPC		0.50
ClinPred		0.098	T
GERP RS		5.2
Varity_R		0.18
gMVP		0.26

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: rs151058774; hg19: chr16-15818834;