chr16-15838241-C-T

Variant names:

• chr16-15838241-C-T
• rs112650390
• NM_002474.3:c.12G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_002474.3(MYH11):​c.12G>A​(p.Lys4Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00082 in 1,614,132 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00084 (1 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 0.0350

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 16-15838241-C-T is Benign according to our data. Variant chr16-15838241-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138362.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=3, Uncertain_significance=1}. Variant chr16-15838241-C-T is described in Lovd as [Likely_benign]. Variant chr16-15838241-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.035 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000578 (88/152272) while in subpopulation AMR AF= 0.000916 (14/15288). AF 95% confidence interval is 0.000612. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.12G>A	p.Lys4Lys	synonymous_variant	Exon 2 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.12G>A	p.Lys4Lys	synonymous_variant	Exon 2 of 43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.12G>A	p.Lys4Lys	synonymous_variant	Exon 2 of 42		NP_001035203.1
MYH11	NM_022844.3	c.12G>A	p.Lys4Lys	synonymous_variant	Exon 2 of 42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.12G>A	p.Lys4Lys	synonymous_variant	Exon 2 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.12G>A	p.Lys4Lys	synonymous_variant	Exon 2 of 43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152154 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000582 AC: 145 AN: 249178 Hom.: 1 AF XY: 0.000630 AC XY: 85 AN XY: 134890

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000744

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000845 AC: 1235 AN: 1461860 Hom.: 1 Cov.: 32 AF XY: 0.000798 AC XY: 580 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00402

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000951

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152272 Hom.: 0 Cov.: 31 AF XY: 0.000564 AC XY: 42 AN XY: 74452

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.000688

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Uncertain:1 Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 28, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 23, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Apr 07, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYH11: BP4, BP7 -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Jan 04, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Feb 24, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: 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. -

Connective tissue disorder Benign:1

Jun 01, 2018

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	2.8
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: rs112650390; hg19: chr16-15932098;