rs112650390

Variant names:

• chr16-15838241-C-T
• rs112650390
• NM_002474.3:c.12G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-15838241-C-T
• chr16-15838241-C-G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_002474.3(MYH11):​c.12G>A​(p.Lys4Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00082 in 1,614,132 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00084 (1 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 0.0350
• 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, 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 16-15838241-C-T is Benign according to our data. Variant chr16-15838241-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 138362.
• BP7: Synonymous conserved (PhyloP=0.035 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000578 (88/152272) while in subpopulation AMR AF = 0.000916 (14/15288). AF 95% confidence interval is 0.000612. There are 0 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 31. 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.12G>A	p.Lys4Lys	synonymous	Exon 2 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.12G>A	p.Lys4Lys	synonymous	Exon 2 of 43	NP_001035202.1	P35749-3
	MYH11	NM_001040114.2		c.12G>A	p.Lys4Lys	synonymous	Exon 2 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.12G>A	p.Lys4Lys	synonymous	Exon 2 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.12G>A	p.Lys4Lys	synonymous	Exon 2 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.12G>A	p.Lys4Lys	synonymous	Exon 2 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152154 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000582 AC: 145 AN: 249178 AF XY: 0.000630

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000744

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000845 AC: 1235 AN: 1461860 Hom.: 1 Cov.: 32 AF XY: 0.000798 AC XY: 580 AN XY: 727240

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000358 AC: 16 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 105 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000951 AC: 1057 AN: 1112006

Other (OTH) AF: 0.000844 AC: 51 AN: 60394

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152272 Hom.: 0 Cov.: 31 AF XY: 0.000564 AC XY: 42 AN XY: 74452

African (AFR) AF: 0.000217 AC: 9 AN: 41556

American (AMR) AF: 0.000916 AC: 14 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

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

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

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000688

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	2.8
DANN	Benign	0.65
PhyloP100		0.035
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: rs112650390; hg19: chr16-15932098;