rs756025504

Variant names:

• chr16-15719226-G-A
• rs756025504
• NM_002474.3:c.5165C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_002474.3(MYH11):​c.5165C>T​(p.Ser1722Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,394 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S1722S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 4.03
• Publications: 0 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics, G2P
• microcephaly with lissencephaly and/or hydranencephaly

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hydranencephaly

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

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

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000263 (4/152036) while in subpopulation EAS AF = 0.000385 (2/5190). AF 95% confidence interval is 0.0000682. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002474.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_002474.3	MANE Select	c.5165C>T	p.Ser1722Leu	missense	Exon 36 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.5186C>T	p.Ser1729Leu	missense	Exon 37 of 43	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.948-4965G>A		intron	N/A	NP_060138.1	Q9NXR1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.5165C>T	p.Ser1722Leu	missense	Exon 36 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.5186C>T	p.Ser1729Leu	missense	Exon 37 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.5186C>T	p.Ser1729Leu	missense	Exon 37 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000385

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

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251110 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461358 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727026

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111988

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152036 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74248

African (AFR) AF: 0.0000242 AC: 1 AN: 41370

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Familial thoracic aortic aneurysm and aortic dissection (3)
-	1	-	Aortic aneurysm, familial thoracic 4 (1)
-	1	-	Aortic aneurysm, familial thoracic 4;C5543466:Visceral myopathy 2;C5543476:Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	0.085
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.38
Sift	Benign	0.20	T
Sift4G	Benign	0.11	T
Polyphen		0.052	B
Vest4		0.63
MutPred		0.38		Loss of phosphorylation at S1722 (P = 0.0098)
MVP		0.68
MPC		0.52
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.32
gMVP		0.44
Mutation Taster		=65/35	polymorphism

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: rs756025504; hg19: chr16-15813083;