rs190675029

chr16-15717331-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_002474.3(MYH11):c.5313C>T(p.Asn1771=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000423 in 1,609,010 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.37

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]

NDE1 (HGNC:17619): (nudE neurodevelopment protein 1) This gene encodes a member of the nuclear distribution E (NudE) family of proteins. The encoded protein is localized at the centrosome and interacts with other centrosome components as part of a multiprotein complex that regulates dynein function. This protein plays an essential role in microtubule organization, mitosis and neuronal migration. Mutations in this gene cause lissencephaly 4, a disorder characterized by lissencephaly, severe brain atrophy, microcephaly, and severe cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 16-15717331-G-A is Benign according to our data. Variant chr16-15717331-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 201038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000405 (59/1456666) while in subpopulation EAS AF= 0.000756 (30/39698). AF 95% confidence interval is 0.000543. There are 0 homozygotes in gnomad4_exome. There are 28 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.5313C>T	p.Asn1771=	synonymous_variant	38/41	ENST00000300036.6
MYH11	NM_001040113.2	c.5334C>T	p.Asn1778=	synonymous_variant	39/43	ENST00000452625.7
NDE1	NM_017668.3	c.948-6860G>A		intron_variant		ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.5313C>T	p.Asn1771=	synonymous_variant	38/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.5334C>T	p.Asn1778=	synonymous_variant	39/43	1	NM_001040113.2
NDE1	ENST00000396354.6	c.948-6860G>A		intron_variant		1	NM_017668.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000972 AC: 24 AN: 246882 Hom.: 0 AF XY: 0.0000822 AC XY: 11 AN XY: 133800

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000405 AC: 59 AN: 1456666 Hom.: 0 Cov.: 33 AF XY: 0.0000386 AC XY: 28 AN XY: 724892

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000756

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000207

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6 AN XY: 74498

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 03, 2019	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. -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 21, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 07, 2021	- -

Aortic aneurysm, familial thoracic 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2023

- -

MYH11-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.77
Dann	Benign	0.88

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: rs190675029; hg19: chr16-15811188;