rs34839877

chr16-15718452-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002474.3(MYH11):c.5172-14C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,547,344 control chromosomes in the GnomAD database, including 1,101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (150 hom., cov: 32)
  • Exomes 𝑓: 0.031 (951 hom.)
• Consequence: MYH11 NM_002474.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.227

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-15718452-G-A is Benign according to our data. Variant chr16-15718452-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15718452-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_001040113.2	c.5193-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000452625.7
MYH11	NM_002474.3	c.5172-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000300036.6
NDE1	NM_017668.3	c.948-5739G>A		intron_variant		ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.5172-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002474.3	P3
NDE1	ENST00000396354.6	c.948-5739G>A		intron_variant		1	NM_017668.3	P1
MYH11	ENST00000452625.7	c.5193-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001040113.2

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5637 AN: 152134 Hom.: 145 Cov.: 32

Gnomad AFR AF: 0.0514

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0323

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.00830

Gnomad SAS AF: 0.0927

Gnomad FIN AF: 0.0311

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0387

GnomAD3 exomes AF: 0.0370 AC: 5797 AN: 156676 Hom.: 202 AF XY: 0.0421 AC XY: 3548 AN XY: 84280

Gnomad AFR exome AF: 0.0561

Gnomad AMR exome AF: 0.0155

Gnomad ASJ exome AF: 0.0275

Gnomad EAS exome AF: 0.0130

Gnomad SAS exome AF: 0.0923

Gnomad FIN exome AF: 0.0346

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.0320

GnomAD4 exome AF: 0.0306 AC: 42672 AN: 1395092 Hom.: 951 Cov.: 31 AF XY: 0.0323 AC XY: 22288 AN XY: 689910

Gnomad4 AFR exome AF: 0.0542

Gnomad4 AMR exome AF: 0.0160

Gnomad4 ASJ exome AF: 0.0269

Gnomad4 EAS exome AF: 0.00818

Gnomad4 SAS exome AF: 0.0844

Gnomad4 FIN exome AF: 0.0310

Gnomad4 NFE exome AF: 0.0269

Gnomad4 OTH exome AF: 0.0344

GnomAD4 genome AF: 0.0373 AC: 5673 AN: 152252 Hom.: 150 Cov.: 32 AF XY: 0.0389 AC XY: 2894 AN XY: 74434

Gnomad4 AFR AF: 0.0517

Gnomad4 AMR AF: 0.0322

Gnomad4 ASJ AF: 0.0265

Gnomad4 EAS AF: 0.00832

Gnomad4 SAS AF: 0.0938

Gnomad4 FIN AF: 0.0311

Gnomad4 NFE AF: 0.0283

Gnomad4 OTH AF: 0.0449

Alfa AF: 0.0314 Hom.: 12

Bravo AF: 0.0355

Asia WGS AF: 0.0570 AC: 198 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 26, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2012	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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	5193-14C>T in intron 37 of MYH11: This variant is not expected to have clinical significance because it has been identified in 5.2% (227/4324) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs34839877). -

Aortic aneurysm, familial thoracic 4 Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Familial aortopathy Benign:1

Benign, criteria provided, single submitter

curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Lissencephaly 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Lissencephaly, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	7.6
Dann	Benign	0.56

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: rs34839877; hg19: chr16-15812309;