rs147605116

Positions:

• chr16-15737451-G-A
• chr16-15737451-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_002474.3(MYH11):​c.3291C>T​(p.Ala1097Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,612,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: MYH11 NM_002474.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9537
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:5
• Conservation: PhyloP100: 2.23

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 16-15737451-G-A is Benign according to our data. Variant chr16-15737451-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201061.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5}. Variant chr16-15737451-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.3291C>T	p.Ala1097Ala	splice_region_variant, synonymous_variant	25/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.3312C>T	p.Ala1104Ala	splice_region_variant, synonymous_variant	26/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.3312C>T	p.Ala1104Ala	splice_region_variant, synonymous_variant	26/42		NP_001035203.1
MYH11	NM_022844.3	c.3291C>T	p.Ala1097Ala	splice_region_variant, synonymous_variant	25/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.3291C>T	p.Ala1097Ala	splice_region_variant, synonymous_variant	25/41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.3312C>T	p.Ala1104Ala	splice_region_variant, synonymous_variant	26/43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000958 AC: 24 AN: 250420 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135494

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: 0.000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000185 AC: 270 AN: 1460008 Hom.: 0 Cov.: 33 AF XY: 0.000178 AC XY: 129 AN XY: 726406

Gnomad4 AFR exome AF: 0.0000299

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: 0.000222

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74320

Gnomad4 AFR AF: 0.0000724

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: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.000128

EpiCase AF: 0.000436

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 02, 2015	The c.3312C>T variant (also known as p.A1104A), located in coding exon 25, results from a C to T substitution at nucleotide position 3312 of the MYH11 gene. This nucleotide substitution does not change the amino acid at codon 1104. However, this change occurs in the third to last base pair of coding exon 25, which gives it potentialto have some effect on normal mRNA splicing.Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable.This variant was previously reported in the SNPDatabase as rs147605116. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.03% (4/12,994) of total alleles studied and 0.05% (4/8,600) ofEuropean American alleles. This nucleotide position is well conserved in available vertebrate species, but the T allele is present in African clawed frog. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 11, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 07, 2022	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2023	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 18, 2020	- -

Marfan syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Apr 25, 2017

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2019

The c.3291C>T variant (also known as p.A1097A), located in coding exon 24 of the MYH11 gene, results from a C to T substitution at nucleotide position 3291. This nucleotide substitution does not change the amino acid at codon 1097. This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 22, 2019

Variant summary: MYH11 c.3312C>T (p.Ala1104Ala) alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.6e-05 in 250420 control chromosomes (gnomAD). The observed variant frequency is approximately 77 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.3312C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1x likely benign and 4x uncertain significance). Based on the evidence outlined above, the variant was classified as likely benign. -

Aortic aneurysm, familial thoracic 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

MYH11-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2023

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
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.86
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: rs147605116; hg19: chr16-15831308; COSMIC: COSV55566700; COSMIC: COSV55566700;