rs587781079

Variant names:

• chr16-15776175-A-G
• rs34341838
• NM_002474.3:c.792T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-15776175-A-G
• chrNT_187607.1-1434160-A-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.792T>C​(p.Tyr264Tyr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0364 in 1,611,816 control chromosomes in the GnomAD database, including 1,344 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (92 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1252 hom.)
• Consequence: MYH11 NM_002474.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0004735
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 2.20
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 16-15776175-A-G is Benign according to our data. Variant chr16-15776175-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138368.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 = 0.0291 (4431/152206) while in subpopulation NFE AF = 0.0453 (3079/68022). AF 95% confidence interval is 0.0439. There are 92 homozygotes in GnomAd4. There are 2161 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 92 AD,AR 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.792T>C	p.Tyr264Tyr	splice_region synonymous	Exon 8 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.813T>C	p.Tyr271Tyr	splice_region synonymous	Exon 9 of 43	NP_001035202.1	P35749-3
	MYH11	NM_001040114.2		c.813T>C	p.Tyr271Tyr	splice_region synonymous	Exon 9 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.792T>C	p.Tyr264Tyr	splice_region synonymous	Exon 8 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.813T>C	p.Tyr271Tyr	splice_region synonymous	Exon 9 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.813T>C	p.Tyr271Tyr	splice_region synonymous	Exon 9 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4432 AN: 152088 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.00746

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0269

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0453

Gnomad OTH AF: 0.0283

GnomAD2 exomes AF: 0.0292 AC: 7339 AN: 251464 AF XY: 0.0290

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.0223

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0405

Gnomad NFE exome AF: 0.0459

Gnomad OTH exome AF: 0.0331

GnomAD4 exome AF: 0.0371 AC: 54186 AN: 1459610 Hom.: 1252 Cov.: 30 AF XY: 0.0363 AC XY: 26377 AN XY: 726284

African (AFR) AF: 0.00658 AC: 220 AN: 33446

American (AMR) AF: 0.0173 AC: 772 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 536 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00634 AC: 547 AN: 86226

European-Finnish (FIN) AF: 0.0434 AC: 2318 AN: 53412

Middle Eastern (MID) AF: 0.0336 AC: 194 AN: 5768

European-Non Finnish (NFE) AF: 0.0429 AC: 47645 AN: 1109886

Other (OTH) AF: 0.0323 AC: 1951 AN: 60320

GnomAD4 genome AF: 0.0291 AC: 4431 AN: 152206 Hom.: 92 Cov.: 32 AF XY: 0.0290 AC XY: 2161 AN XY: 74424

African (AFR) AF: 0.00744 AC: 309 AN: 41516

American (AMR) AF: 0.0268 AC: 410 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4826

European-Finnish (FIN) AF: 0.0412 AC: 437 AN: 10600

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0453 AC: 3079 AN: 68022

Other (OTH) AF: 0.0280 AC: 59 AN: 2110

Alfa AF: 0.0362 Hom.: 151

Bravo AF: 0.0263

Asia WGS AF: 0.00375 AC: 14 AN: 3478

EpiCase AF: 0.0417

EpiControl AF: 0.0439

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Aortic aneurysm, familial thoracic 4 (5)
-	-	4	not specified (4)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.6
DANN	Benign	0.63
PhyloP100		2.2
Mutation Taster		=72/28	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00047
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.34		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34341838; hg19: chr16-15870032; COSMIC: COSV55553779;