rs61734198

Variant names:

• chr16-15757983-C-T
• rs61734198
• NM_002474.3:c.1419G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002474.3(MYH11):​c.1419G>A​(p.Gln473Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,036 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00086 (10 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 2.20
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 16-15757983-C-T is Benign according to our data. Variant chr16-15757983-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00483 (736/152316) while in subpopulation AFR AF = 0.0152 (631/41566). AF 95% confidence interval is 0.0142. There are 2 homozygotes in GnomAd4. There are 374 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1419G>A	p.Gln473Gln	synonymous	Exon 13 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.1440G>A	p.Gln480Gln	synonymous	Exon 14 of 43	NP_001035202.1	P35749-3
	MYH11	NM_001040114.2		c.1440G>A	p.Gln480Gln	synonymous	Exon 14 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.1419G>A	p.Gln473Gln	synonymous	Exon 13 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.1440G>A	p.Gln480Gln	synonymous	Exon 14 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.1440G>A	p.Gln480Gln	synonymous	Exon 14 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.00480 AC: 731 AN: 152198 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00153 AC: 384 AN: 251482 AF XY: 0.00122

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000861 AC: 1258 AN: 1461720 Hom.: 10 Cov.: 32 AF XY: 0.000756 AC XY: 550 AN XY: 727148

African (AFR) AF: 0.0171 AC: 572 AN: 33476

American (AMR) AF: 0.00228 AC: 102 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 120 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

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

Middle Eastern (MID) AF: 0.000711 AC: 4 AN: 5626

European-Non Finnish (NFE) AF: 0.000303 AC: 337 AN: 1112012

Other (OTH) AF: 0.00204 AC: 123 AN: 60382

GnomAD4 genome AF: 0.00483 AC: 736 AN: 152316 Hom.: 2 Cov.: 31 AF XY: 0.00502 AC XY: 374 AN XY: 74486

African (AFR) AF: 0.0152 AC: 631 AN: 41566

American (AMR) AF: 0.00353 AC: 54 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00323 Hom.: 3

Bravo AF: 0.00558

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	2	Aortic aneurysm, familial thoracic 4 (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.6
DANN	Benign	0.89
PhyloP100		2.2
Mutation Taster		=97/3	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: rs61734198; hg19: chr16-15851840;