rs113667224

chr16-15704110-T-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_002474.3(MYH11):c.5800A>T(p.Thr1934Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,614,030 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (5 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: -0.451

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH11
• BP4: Computational evidence support a benign effect (MetaRNN=0.005936742).
• BP6: Variant 16-15704110-T-A is Benign according to our data. Variant chr16-15704110-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201044.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Uncertain_significance=1, Benign=2}. Variant chr16-15704110-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00159 (242/152212) while in subpopulation NFE AF= 0.00291 (198/68020). AF 95% confidence interval is 0.00258. There are 0 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.5800A>T	p.Thr1934Ser	missense_variant	41/41	ENST00000300036.6
MYH11	NM_001040113.2	c.*22A>T		3_prime_UTR_variant	43/43	ENST00000452625.7
NDE1	NM_017668.3	c.947+7250T>A		intron_variant		ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.5800A>T	p.Thr1934Ser	missense_variant	41/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.*22A>T		3_prime_UTR_variant	43/43	1	NM_001040113.2
NDE1	ENST00000396354.6	c.947+7250T>A		intron_variant		1	NM_017668.3	P1

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00291

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00136 AC: 342 AN: 251458 Hom.: 0 AF XY: 0.00129 AC XY: 175 AN XY: 135906

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00252 AC: 3678 AN: 1461818 Hom.: 5 Cov.: 31 AF XY: 0.00243 AC XY: 1769 AN XY: 727214

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000468

Gnomad4 NFE exome AF: 0.00319

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00159 AC: 242 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74422

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00291

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00251 Hom.: 0

Bravo AF: 0.00170

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00124 AC: 151

EpiCase AF: 0.00349

EpiControl AF: 0.00231

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 30, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 05, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2021	This variant is associated with the following publications: (PMID: 28600387, 25500235, 25188385, 30122538, 32859249) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 19, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MYH11: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 16, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 20, 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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2022

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. -

Aortic aneurysm, familial thoracic 6 Benign:1

Likely benign, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Mar 11, 2015

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	12
Dann	Benign	0.93
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D;D;D;N;N;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.11	N;N
REVEL	Benign	0.25
Sift	Benign	0.35	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.0	.;B
Vest4		0.030
MutPred		0.14		.;Gain of glycosylation at P1938 (P = 0.2403);
MVP		0.53
MPC		0.16
ClinPred		0.0054	T
GERP RS		1.7
Varity_R		0.037
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs113667224; hg19: chr16-15797967;