NM_002474.3:c.503-14_503-12delCTT

Variant names:

• chr16-15798698-AAAG-A
• rs141564071
• NM_002474.3:c.503-14_503-12delCTT

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_503-12delCTT variant causes a 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 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 rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.503-14_503-12delCTT		intron_variant	Intron 3 of 40	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.503-14_503-12delCTT		intron_variant	Intron 3 of 42	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.503-14_503-12delCTT		intron_variant	Intron 3 of 41		NP_001035203.1
MYH11	NM_022844.3	c.503-14_503-12delCTT		intron_variant	Intron 3 of 41		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.503-14_503-12delCTT		intron_variant	Intron 3 of 40	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.503-14_503-12delCTT		intron_variant	Intron 3 of 42	1	NM_001040113.2	ENSP00000407821.2

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

Mar 12, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Sep 12, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Mar 19, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;