rs369196744

Positions:

chr16-15745153-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP3_StrongBS1_Supporting

The NM_002474.3(MYH11):c.2496G>C(p.Trp832Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

MYH11
NM_002474.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 7.89

Variant links:

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]

MYH11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000623 (91/1461830) while in subpopulation NFE AF= 0.0000791 (88/1111990). AF 95% confidence interval is 0.0000652. There are 0 homozygotes in gnomad4_exome. There are 45 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3 link	c.2496G>C	p.Trp832Cys	missense_variant	20/41	ENST00000300036.6	NP_002465.1	P35749-1A0A024QZJ4
MYH11	NM_001040113.2 link	c.2517G>C	p.Trp839Cys	missense_variant	21/43	ENST00000452625.7	NP_001035202.1	P35749-3
MYH11	NM_001040114.2 link	c.2517G>C	p.Trp839Cys	missense_variant	21/42		NP_001035203.1	P35749-2
MYH11	NM_022844.3 link	c.2496G>C	p.Trp832Cys	missense_variant	20/42		NP_074035.1	P35749-4A0A024QZJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6 link	c.2496G>C	p.Trp832Cys	missense_variant	20/41	1	NM_002474.3	ENSP00000300036.5		P35749-1
MYH11	ENST00000452625.7 link	c.2517G>C	p.Trp839Cys	missense_variant	21/43	1	NM_001040113.2	ENSP00000407821.2		P35749-3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251436

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

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:

0.0000623

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000791

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000965

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 13, 2023	This missense variant replaces tryptophan with cysteine at codon 839 of the MYH11 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with Marfan syndrome, who also carried a pathogenic truncation variant in the FBN1 gene (PMID: 25944730). This variant has also been reported in one individual affected with inherited thoracic aortic aneurysm disease, who also carried a pathogenic c.4210+1G>A variant in the FBN1 gene (doi:10.1016/j.hlc.2015.06.677). This variant has been identified in 5/282828 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 31, 2022	The p.W832C variant (also known as c.2496G>C), located in coding exon 19 of the MYH11 gene, results from a G to C substitution at nucleotide position 2496. The tryptophan at codon 832 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant co-occurred with a frameshift variant in the FBN1 gene in an individual reported to have Marfan syndrome (Wooderchak-Donahue W et al. Am J Med Genet A, 2015 Aug;167A:1747-57). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 26, 2023	This missense variant replaces tryptophan with cysteine at codon 839 of the MYH11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Marfan syndrome and thoracic aortic aneurysm, who also carried a pathogenic c.4210+1G>A variant in the FBN1 gene (Robertson et al., 2015). This variant has been identified in 5/282828 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Aortic aneurysm, familial thoracic 4

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with megacystis-microcolon-intestinal hypoperistalsis syndrome 2 (MMIHS; MIM#619351). The disease mechanism for chronic intestinal pseudo-obstruction (CIPO), also known as visceral myopathy 2 (MIM#619350), and aortic aneurysm, familial thoracic 4 (AAFT; MIM#132900) is unclear, however loss of function and dominant negative have been suggested, respectively (PMID: 31944481). (I) 0108 - This gene is associated with both recessive and dominant disease. MMIHS is an autosomal recessive form of disease caused by both missense variants and those resulting in a premature termination codon. AAFT is autosomal dominant and has been reported in patients with splice, missense and inframe deletion variants. CIPO is autosomal dominant and has only been reported in patients with protein elongation variants exclusive to isoform SM2 (PMIDs: 31389005, 31944481). (I) 0112 - The aortic aneurysm associated with this gene has incomplete penetrance (PMIDs: 17666408, 22968129). (I) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 & v3) <0.001 (9 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS by multiple clinical testing laboratories, including in two individuals with aortic aneurysm or mildly dilated ascending aorta, three individuals with Ehlers Danlos syndrome or “connective tissue and skeletal symptoms”, and multiple individuals without thoracic aortic aneurysm and aortic dissection (ClinVar, personal communication). It has also been reported as a VUS in two individuals with Marfan syndrome, each of whom also had a disease-causing FBN1 variant (PMID: 25944730; ClinVar, personal communication). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 07, 2022	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 839 of the MYH11 protein (p.Trp839Cys). This variant is present in population databases (rs369196744, gnomAD 0.008%). This missense change has been observed in individual(s) with Marfan syndrome. However this individual also carried a pathogenic FBN1 variant (PMID: 25944730). ClinVar contains an entry for this variant (Variation ID: 180417). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2023	Has been reported in a patient with Marfan syndrome, who also carried a pathogenic variant in the FBN1 gene (Wooderchak-Donahue et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25944730) -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 27, 2021	- -

Marfan syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 11, 2015

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 23, 2024

Variant summary: MYH11 c.2517G>C (p.Trp839Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 1614046 control chromosomes. The observed variant frequency is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Thoracic Aortic Aneurysms And Dissections phenotype (1.3e-05). c.2517G>C has been reported in the literature in an individual with a clinical diagnosis of Marfan Syndrome who also had a co-occurring pathogenic variant in FBN1 (c.7254dupT, p.Val2419CysfsX3), providing supporting evidence for a benign role (Wooderchak-Donahue_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25944730).ClinVar contains an entry for this variant (Variation ID: 180417). 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

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

.;.;.;D

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Pathogenic

3.5

.;.;H;H

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-12

D;D;.;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D;.;D

Sift4G

Uncertain

0.018

D;D;D;D

Polyphen

1.0

.;.;.;D

Vest4

0.93

MutPred

0.73

.;.;Gain of catalytic residue at R830 (P = 0.149);Gain of catalytic residue at R830 (P = 0.149);

MVP

0.91

MPC

2.3

ClinPred

1.0

GERP RS

4.8

Varity_R

0.86

gMVP

0.91

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over