rs112834652

Positions:

• chr16-15753410-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002474.3(MYH11):​c.1848C>T​(p.Ala616=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000819 in 1,614,016 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (9 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.48

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 16-15753410-G-A is Benign according to our data. Variant chr16-15753410-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 318170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.48 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.1848C>T	p.Ala616=	synonymous_variant	15/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.1869C>T	p.Ala623=	synonymous_variant	16/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.1869C>T	p.Ala623=	synonymous_variant	16/42		NP_001035203.1
MYH11	NM_022844.3	c.1848C>T	p.Ala616=	synonymous_variant	15/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.1848C>T	p.Ala616=	synonymous_variant	15/41	1	NM_002474.3	ENSP00000300036	P3
MYH11	ENST00000452625.7	c.1869C>T	p.Ala623=	synonymous_variant	16/43	1	NM_001040113.2	ENSP00000407821

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 152112 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00184 AC: 462 AN: 251470 Hom.: 1 AF XY: 0.00168 AC XY: 228 AN XY: 135914

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000733 AC: 1071 AN: 1461786 Hom.: 9 Cov.: 32 AF XY: 0.000667 AC XY: 485 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0178

Gnomad4 NFE exome AF: 0.0000683

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.00165 AC: 251 AN: 152230 Hom.: 4 Cov.: 31 AF XY: 0.00269 AC XY: 200 AN XY: 74420

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0225

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000426 Hom.: 0

Bravo AF: 0.0000604

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 22, 2017	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 13, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aortic aneurysm, familial thoracic 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.1
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs112834652; hg19: chr16-15847267; COSMIC: COSV55551188;