rs111936548

chr16-15756358-T-C

Variant summary

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

The NM_002474.3(MYH11):c.1732A>G(p.Ile578Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00065 in 1,614,082 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (2 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 2.11

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]

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=0.044097632).
• BP6: Variant 16-15756358-T-C is Benign according to our data. Variant chr16-15756358-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201024.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=6, Uncertain_significance=1}. Variant chr16-15756358-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000493 (75/152204) while in subpopulation NFE AF= 0.000882 (60/68020). AF 95% confidence interval is 0.000703. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.1732A>G	p.Ile578Val	missense_variant	14/41	ENST00000300036.6
MYH11	NM_001040113.2	c.1753A>G	p.Ile585Val	missense_variant	15/43	ENST00000452625.7
MYH11	NM_001040114.2	c.1753A>G	p.Ile585Val	missense_variant	15/42
MYH11	NM_022844.3	c.1732A>G	p.Ile578Val	missense_variant	14/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.1732A>G	p.Ile578Val	missense_variant	14/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.1753A>G	p.Ile585Val	missense_variant	15/43	1	NM_001040113.2

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000617 AC: 155 AN: 251388 Hom.: 1 AF XY: 0.000692 AC XY: 94 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000666 AC: 974 AN: 1461878 Hom.: 2 Cov.: 35 AF XY: 0.000642 AC XY: 467 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.000772

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74436

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000849

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000812 Hom.: 0

Bravo AF: 0.000400

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000799 AC: 97

EpiCase AF: 0.000382

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 14, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 22, 2019	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	May 14, 2019	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 24, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 29, 2016	Variant summary: This c.1753A>G variant affects a non-conserved nucleotide, resulting in amino acid change from Ile to Val. 3/3 in-silico tools predict this variant to be benign (SNPs&GO and Mutation Taster not captured here due to low reliability index and p-value, respectively). The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 97/121158 (1/1249), which exceeds the predicted maximum expected allele frequency for a pathogenic MYH11 variant of 1/769230. The variant of interest, to our knowledge, has not been reported in affected individuals via publications, although a reputable clinical laboratory cites the variant as "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

MYH11-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2021

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	21
Dann	Benign	0.95
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.044	T;T;T;T
MetaSVM	Benign	-0.61	T
MutationTaster	Benign	0.50	N;N;N;N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.56	N;N;.;N
REVEL	Benign	0.22
Sift	Benign	0.44	T;T;.;T
Sift4G	Benign	0.80	T;T;T;T
Polyphen		0.0010	.;.;.;B
Vest4		0.15
MVP		0.51
MPC		0.63
ClinPred		0.032	T
GERP RS		5.4
Varity_R		0.044
gMVP		0.11

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: rs111936548; hg19: chr16-15850215;