rs587781049

chr16-15745112-T-CchrNT_187607.1-1403122-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_002474.3(MYH11):c.2520+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00398 in 1,605,218 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (18 hom.)
• Consequence: MYH11 NM_002474.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.09

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-15745112-T-C is Benign according to our data. Variant chr16-15745112-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 138331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15745112-T-C is described in Lovd as [Likely_benign]. Variant chr16-15745112-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00367 (559/152310) while in subpopulation NFE AF= 0.00426 (290/68024). AF 95% confidence interval is 0.00386. There are 1 homozygotes in gnomad4. There are 314 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_001040113.2	c.2541+17A>G		intron_variant		ENST00000452625.7
MYH11	NM_002474.3	c.2520+17A>G		intron_variant		ENST00000300036.6
MYH11	NM_001040114.2	c.2541+17A>G		intron_variant
MYH11	NM_022844.3	c.2520+17A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.2520+17A>G		intron_variant		1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.2541+17A>G		intron_variant		1	NM_001040113.2

Frequencies

GnomAD3 genomes AF: 0.00367 AC: 559 AN: 152192 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00370 AC: 929 AN: 251036 Hom.: 1 AF XY: 0.00391 AC XY: 531 AN XY: 135718

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0160

Gnomad NFE exome AF: 0.00443

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00401 AC: 5828 AN: 1452908 Hom.: 18 Cov.: 31 AF XY: 0.00398 AC XY: 2877 AN XY: 723412

Gnomad4 AFR exome AF: 0.000540

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0141

Gnomad4 NFE exome AF: 0.00433

Gnomad4 OTH exome AF: 0.00308

GnomAD4 genome AF: 0.00367 AC: 559 AN: 152310 Hom.: 1 Cov.: 33 AF XY: 0.00422 AC XY: 314 AN XY: 74482

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0165

Gnomad4 NFE AF: 0.00426

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00269 Hom.: 0

Bravo AF: 0.00264

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2013	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. -
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 02, 2019	Variant summary: MYH11 c.2541+17A>G alters a non-conserved 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 canonical splice site but several tools predict that this variant abolishes a cryptic 3' acceptor site and creates a new one. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0037 in 251036 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 2960 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.2541+17A>G in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign (1x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as benign. -

Aortic aneurysm, familial thoracic 4 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Nov 09, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Mar 17, 2015	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.47
Dann	Benign	0.39

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: rs185697714; hg19: chr16-15838969;