rs35035518

chr16-15741764-G-A

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.2648C>T(p.Ser883Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000274 in 1,614,132 control chromosomes in the GnomAD database, including 1 homozygotes. 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). Synonymous variant affecting the same amino acid position (i.e. S883S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 2.25

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]

(HGNC:):

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=0.012095034).
• BP6: Variant 16-15741764-G-A is Benign according to our data. Variant chr16-15741764-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201056.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=3, Uncertain_significance=1}. Variant chr16-15741764-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000272 (398/1461880) while in subpopulation AFR AF= 0.000896 (30/33480). AF 95% confidence interval is 0.000644. There are 0 homozygotes in gnomad4_exome. There are 207 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.2648C>T	p.Ser883Leu	missense_variant	21/41	ENST00000300036.6
MYH11	NM_001040113.2	c.2669C>T	p.Ser890Leu	missense_variant	22/43	ENST00000452625.7
MYH11	NM_001040114.2	c.2669C>T	p.Ser890Leu	missense_variant	22/42
MYH11	NM_022844.3	c.2648C>T	p.Ser883Leu	missense_variant	21/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.2648C>T	p.Ser883Leu	missense_variant	21/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.2669C>T	p.Ser890Leu	missense_variant	22/43	1	NM_001040113.2
	ENST00000577048.1	n.523G>A		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152134 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000390 AC: 98 AN: 251478 Hom.: 1 AF XY: 0.000375 AC XY: 51 AN XY: 135914

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00605

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000272 AC: 398 AN: 1461880 Hom.: 0 Cov.: 30 AF XY: 0.000285 AC XY: 207 AN XY: 727238

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00616

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152252 Hom.: 1 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74440

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000633 Hom.: 0

Bravo AF: 0.000340

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

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

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 11, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 20, 2018	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. -

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MYH11: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 04, 2020

Variant summary: MYH11 c.2669C>T (p.Ser890Leu) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) 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 0.00039 in 251478 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 312 fold of 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. To our knowledge, no occurrence of c.2669C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (2x), likely benign (2x) and benign (2x). Based on the evidence outlined above, the variant was classified as likely benign. -

MYH11-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2024

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	0.063
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.4	N;N;.;N
REVEL	Benign	0.10
Sift	Benign	0.11	T;T;.;T
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.0	.;.;.;B
Vest4		0.30
MVP		0.41
MPC		0.67
ClinPred		0.017	T
GERP RS		4.1
Varity_R		0.069
gMVP		0.20

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: rs35035518; hg19: chr16-15835621; COSMIC: COSV100260569;