rs141564071

chr16-15798698-AAAG-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002474.3(MYH11):c.503-14_503-12del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00614 in 1,613,096 control chromosomes in the GnomAD database, including 423 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (208 hom., cov: 31)
  • Exomes 𝑓: 0.0038 (215 hom.)
• Consequence: MYH11 NM_002474.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.96

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 -16 ACMG points.

• BP6: Variant 16-15798698-AAAG-A is Benign according to our data. Variant chr16-15798698-AAAG-A is described in ClinVar as [Likely_benign]. Clinvar id is 36624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15798698-AAAG-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_001040113.2	c.503-14_503-12del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000452625.7
MYH11	NM_002474.3	c.503-14_503-12del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000300036.6
MYH11	NM_001040114.2	c.503-14_503-12del		splice_polypyrimidine_tract_variant, intron_variant
MYH11	NM_022844.3	c.503-14_503-12del		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.503-14_503-12del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.503-14_503-12del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001040113.2

Frequencies

GnomAD3 genomes AF: 0.0288 AC: 4372 AN: 151806 Hom.: 206 Cov.: 31

Gnomad AFR AF: 0.0972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.00876 AC: 2199 AN: 251078 Hom.: 91 AF XY: 0.00679 AC XY: 922 AN XY: 135758

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.00490

Gnomad ASJ exome AF: 0.0278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000757

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00378 AC: 5517 AN: 1461180 Hom.: 215 AF XY: 0.00329 AC XY: 2388 AN XY: 726926

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.00558

Gnomad4 ASJ exome AF: 0.0285

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000487

Gnomad4 OTH exome AF: 0.00901

GnomAD4 genome AF: 0.0289 AC: 4384 AN: 151916 Hom.: 208 Cov.: 31 AF XY: 0.0274 AC XY: 2035 AN XY: 74266

Gnomad4 AFR AF: 0.0972

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0228 Hom.: 24

Bravo AF: 0.0335

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Mar 12, 2015	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 12, 2018	Variant summary: MYH11 c.503-14_503-12delCTT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.011 in 276760 control chromosomes, predominantly at a frequency of 0.1 within the African subpopulation in the gnomAD database, including 121 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 79999.95 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 a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.503-14_503-12delCTT in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 19, 2018	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

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: rs141564071; hg19: chr16-15892555;