rs185661462

Variant names:

• chr16-15771688-T-C
• rs185661462
• NM_002474.3:c.914A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002474.3(MYH11):​c.914A>G​(p.Asn305Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,614,138 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N305K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00026 (6 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: -0.353
• Publications: 4 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, Unknown 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
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• visceral myopathy 2

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004294157).
• BP6: Variant 16-15771688-T-C is Benign according to our data. Variant chr16-15771688-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201103.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000427 (65/152244) while in subpopulation EAS AF = 0.00965 (50/5180). AF 95% confidence interval is 0.00752. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002474.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_002474.3	MANE Select	c.914A>G	p.Asn305Ser	missense	Exon 9 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.935A>G	p.Asn312Ser	missense	Exon 10 of 43	NP_001035202.1	P35749-3
	MYH11	NM_001040114.2		c.935A>G	p.Asn312Ser	missense	Exon 10 of 42	NP_001035203.1	P35749-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.914A>G	p.Asn305Ser	missense	Exon 9 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.935A>G	p.Asn312Ser	missense	Exon 10 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.935A>G	p.Asn312Ser	missense	Exon 10 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152126 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00944

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000684 AC: 172 AN: 251434 AF XY: 0.000677

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00832

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000262 AC: 383 AN: 1461894 Hom.: 6 Cov.: 32 AF XY: 0.000231 AC XY: 168 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00484 AC: 192 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112012

Other (OTH) AF: 0.00260 AC: 157 AN: 60396

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152244 Hom.: 0 Cov.: 30 AF XY: 0.000417 AC XY: 31 AN XY: 74428

African (AFR) AF: 0.0000241 AC: 1 AN: 41552

American (AMR) AF: 0.000327 AC: 5 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00965 AC: 50 AN: 5180

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000904 Hom.: 3

Bravo AF: 0.000366

ExAC AF: 0.000568 AC: 69

Asia WGS AF: 0.0140 AC: 48 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	Aortic aneurysm, familial thoracic 4 (4)
-	1	2	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)
-	-	1	MYH11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.0
DANN	Benign	0.51
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.92	N
PhyloP100		-0.35
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.14
Sift	Benign	0.70	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.064
MVP		0.32
MPC		0.60
ClinPred		0.011	T
GERP RS		-6.5
Varity_R		0.050
gMVP		0.12
Mutation Taster		=99/1	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: rs185661462; hg19: chr16-15865545;