rs185697714

Variant names:

• chr16-15745112-T-C
• rs185697714
• NM_002474.3:c.2520+17A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Publications: 1 publications found

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]

MYH11 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• aortic aneurysm, familial thoracic 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• megacystis-microcolon-intestinal hypoperistalsis syndrome 2

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• megacystis-microcolon-intestinal hypoperistalsis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• visceral myopathy 2

  Inheritance: AR, AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 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.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.2520+17A>G		intron_variant	Intron 20 of 40	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.2541+17A>G		intron_variant	Intron 21 of 42	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.2541+17A>G		intron_variant	Intron 21 of 41		NP_001035203.1
MYH11	NM_022844.3	c.2520+17A>G		intron_variant	Intron 20 of 41		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.2520+17A>G		intron_variant	Intron 20 of 40	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.2541+17A>G		intron_variant	Intron 21 of 42	1	NM_001040113.2	ENSP00000407821.2

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

GnomAD2 exomes AF: 0.00370 AC: 929 AN: 251036 AF XY: 0.00391

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 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

African (AFR) AF: 0.000540 AC: 18 AN: 33348

American (AMR) AF: 0.00197 AC: 88 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000767 AC: 2 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86108

European-Finnish (FIN) AF: 0.0141 AC: 750 AN: 53174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00433 AC: 4784 AN: 1103946

Other (OTH) AF: 0.00308 AC: 185 AN: 60126

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

African (AFR) AF: 0.000722 AC: 30 AN: 41574

American (AMR) AF: 0.00359 AC: 55 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0165 AC: 175 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00426 AC: 290 AN: 68024

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00281 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

Jan 30, 2013

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 02, 2019

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.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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 09, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Oct 19, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: 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	-0.92
CADD	Benign	0.47
DANN	Benign	0.39
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs185697714; hg19: chr16-15838969;