16-15715248-C-T

Position:

• chr16-15715248-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The ENST00000300036.6(MYH11):​c.5529G>A​(p.Ser1843=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 1,614,068 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: MYH11 ENST00000300036.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:11
• Conservation: PhyloP100: -5.30

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 16-15715248-C-T is Benign according to our data. Variant chr16-15715248-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197068.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=3, Uncertain_significance=4}.
• BP7: Synonymous conserved (PhyloP=-5.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000367 (537/1461814) while in subpopulation MID AF= 0.00191 (11/5760). AF 95% confidence interval is 0.00107. There are 0 homozygotes in gnomad4_exome. There are 278 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.5529G>A	p.Ser1843=	synonymous_variant	39/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.5550G>A	p.Ser1850=	synonymous_variant	40/43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.948-8943C>T		intron_variant		ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.5529G>A	p.Ser1843=	synonymous_variant	39/41	1	NM_002474.3	ENSP00000300036	P3
MYH11	ENST00000452625.7	c.5550G>A	p.Ser1850=	synonymous_variant	40/43	1	NM_001040113.2	ENSP00000407821
NDE1	ENST00000396354.6	c.948-8943C>T		intron_variant		1	NM_017668.3	ENSP00000379642	P1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000529 AC: 133 AN: 251360 Hom.: 0 AF XY: 0.000552 AC XY: 75 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.000413

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000367 AC: 537 AN: 1461814 Hom.: 0 Cov.: 34 AF XY: 0.000382 AC XY: 278 AN XY: 727216

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00700

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000248

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74438

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00100 Hom.: 0

Bravo AF: 0.000476

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MYH11: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 13, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 04, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Aortic aneurysm, familial thoracic 4 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Lissencephaly, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Mar 23, 2020

- -

MYH11-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 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). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2015

This alteration is classified as likely benign based on a combination of the following: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.41
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146024732; hg19: chr16-15809105;