rs2242549

Variant names:

• chr16-15704353-G-T
• rs2242549
• NM_002474.3:c.5787-230C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002474.3(MYH11):​c.5787-230C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 151,856 control chromosomes in the GnomAD database, including 22,806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.54 (22806 hom., cov: 32)
• Consequence: MYH11 NM_002474.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.252
• Publications: 8 publications found

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]

NDE1 Gene-Disease associations (from GenCC):

• lissencephaly 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• hydranencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• microlissencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• NDE1-related microhydranencephaly

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-15704353-G-T is Benign according to our data. Variant chr16-15704353-G-T is described in ClinVar as [Benign]. Clinvar id is 678516.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.5787-230C>A		intron_variant	Intron 40 of 40	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.*9-230C>A		intron_variant	Intron 42 of 42	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.947+7493G>T		intron_variant	Intron 8 of 8	ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.5787-230C>A		intron_variant	Intron 40 of 40	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.*9-230C>A		intron_variant	Intron 42 of 42	1	NM_001040113.2	ENSP00000407821.2
NDE1	ENST00000396354.6	c.947+7493G>T		intron_variant	Intron 8 of 8	1	NM_017668.3	ENSP00000379642.1

Frequencies

GnomAD3 genomes AF: 0.540 AC: 81871 AN: 151740 Hom.: 22795 Cov.: 32

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.674

Gnomad EAS AF: 0.594

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.598

Gnomad OTH AF: 0.567

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.539 AC: 81919 AN: 151856 Hom.: 22806 Cov.: 32 AF XY: 0.541 AC XY: 40147 AN XY: 74200

African (AFR) AF: 0.374 AC: 15485 AN: 41384

American (AMR) AF: 0.614 AC: 9361 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 2335 AN: 3464

East Asian (EAS) AF: 0.595 AC: 3062 AN: 5144

South Asian (SAS) AF: 0.625 AC: 3013 AN: 4818

European-Finnish (FIN) AF: 0.577 AC: 6075 AN: 10522

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.598 AC: 40649 AN: 67954

Other (OTH) AF: 0.563 AC: 1187 AN: 2110

Alfa AF: 0.555 Hom.: 3637

Bravo AF: 0.535

Asia WGS AF: 0.592 AC: 2060 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.49
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2242549; hg19: chr16-15798210;