rs113696032

Variant names:

• chr16-15740155-C-A
• rs113696032
• NM_002474.3:c.2893G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-15740155-C-A
• chr16-15740155-C-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_002474.3(MYH11):​c.2893G>T​(p.Ala965Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000295 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A965V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:9
• Conservation: PhyloP100: 5.82
• Publications: 7 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1176061).
• BP6: Variant 16-15740155-C-A is Benign according to our data. Variant chr16-15740155-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201058.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000309 (47/152220) while in subpopulation NFE AF = 0.000603 (41/68042). AF 95% confidence interval is 0.000457. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2893G>T	p.Ala965Ser	missense	Exon 23 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.2914G>T	p.Ala972Ser	missense	Exon 24 of 43	NP_001035202.1	P35749-3
	MYH11	NM_001040114.2		c.2914G>T	p.Ala972Ser	missense	Exon 24 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.2893G>T	p.Ala965Ser	missense	Exon 23 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.2914G>T	p.Ala972Ser	missense	Exon 24 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.2914G>T	p.Ala972Ser	missense	Exon 24 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000350 AC: 88 AN: 251494 AF XY: 0.000316

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000677

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000293 AC: 429 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.000292 AC XY: 212 AN XY: 727242

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000358 AC: 398 AN: 1112000

Other (OTH) AF: 0.000232 AC: 14 AN: 60396

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74370

African (AFR) AF: 0.0000965 AC: 4 AN: 41446

American (AMR) AF: 0.000131 AC: 2 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000530 Hom.: 0

Bravo AF: 0.000268

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000395 AC: 48

EpiCase AF: 0.000927

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	Aortic aneurysm, familial thoracic 4 (5)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	2	1	not provided (3)
-	-	2	not specified (2)
-	1	-	MYH11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.034
Eigen_PC	Benign	0.096
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.40
Sift	Benign	0.23	T
Sift4G	Benign	0.37	T
Polyphen		0.0030	B
Vest4		0.24
MVP		0.75
MPC		0.17
ClinPred		0.022	T
GERP RS		4.0
Varity_R		0.13
gMVP		0.18
Mutation Taster		=84/16	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: rs113696032; hg19: chr16-15834012; COSMIC: COSV99037603; COSMIC: COSV99037603;