rs587781076

Positions:

• chr16-15823370-T-C
• chrNT_187607.1-1481355-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000300036.6(MYH11):​c.387A>G​(p.Lys129=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,614,070 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (25 hom., cov: 33)
  • Exomes 𝑓: 0.00093 (16 hom.)
• Consequence: MYH11 ENST00000300036.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.500

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 16-15823370-T-C is Benign according to our data. Variant chr16-15823370-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 138365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15823370-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00955 (1453/152180) while in subpopulation AFR AF= 0.0327 (1358/41512). AF 95% confidence interval is 0.0313. There are 25 homozygotes in gnomad4. There are 713 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.387A>G	p.Lys129=	synonymous_variant	3/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.387A>G	p.Lys129=	synonymous_variant	3/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.387A>G	p.Lys129=	synonymous_variant	3/42		NP_001035203.1
MYH11	NM_022844.3	c.387A>G	p.Lys129=	synonymous_variant	3/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.387A>G	p.Lys129=	synonymous_variant	3/41	1	NM_002474.3	ENSP00000300036	P3
MYH11	ENST00000452625.7	c.387A>G	p.Lys129=	synonymous_variant	3/43	1	NM_001040113.2	ENSP00000407821

Frequencies

GnomAD3 genomes AF: 0.00944 AC: 1436 AN: 152062 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00247 AC: 621 AN: 251490 Hom.: 8 AF XY: 0.00195 AC XY: 265 AN XY: 135920

Gnomad AFR exome AF: 0.0328

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000934 AC: 1365 AN: 1461890 Hom.: 16 Cov.: 34 AF XY: 0.000847 AC XY: 616 AN XY: 727246

Gnomad4 AFR exome AF: 0.0308

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000791

Gnomad4 OTH exome AF: 0.00257

GnomAD4 genome AF: 0.00955 AC: 1453 AN: 152180 Hom.: 25 Cov.: 33 AF XY: 0.00958 AC XY: 713 AN XY: 74400

Gnomad4 AFR AF: 0.0327

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00474 Hom.: 4

Bravo AF: 0.0107

Asia WGS AF: 0.00404 AC: 15 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2014	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, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:4

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 20, 2015	This alteration is classified as 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	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 06, 2016	Variant summary: The MYH11 c.387A>G (p.Lys129Lys) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SRp40. However, these predictions have yet to be confirmed by functional studies. This variant was found in 363/121412 control chromosomes (4 homozygotes) at a frequency of 0.0029898, which is approximately 2392 times the estimated maximal expected allele frequency of a pathogenic MYH11 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Aortic aneurysm, familial thoracic 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.65

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: rs78754138; hg19: chr16-15917227;